LIBRARY 


UNIVERSITY  OF  CALIFORNIA 


PROGRESS 

..IN... 


Alkaloidal  Chemistry 


'DURING  THE  YEAR  (904. 


...BY... 


H.  M.  GORDIN. 


MILWAUKEE, 

Pharmaceutical  Review  Publishing  Co. 
1905. 


Pharmaceutical  Review  Publ.  Co 


Pharmaceutical  Review.  Formerly  the  Pharmaceutische  Rund- 
schau of  New  York  City,  established  in  December  1882  and 
edited  up  to  December  1895  by  Dr.  Fr.  Hoffmann  in  the  German 
language.  Edited  since  January  1896  in  the  English  language 
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the  ablest  representatives  of  pharmaceutical  science  in  the 

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of  Leipzig,  is  universally  acknowledged  to  be  the  most  authori- 
tative and  elaborate  work  on  the  subject.  The  English  trans- 
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Pharmaceutical   Science   Series. 


EDITED     BY 

EDWARD  KREMERS. 


MONOGRAPHS. 
No.  10. 


MILWAUKEE. 

Pharmaceutical  Review  Publishing  Cof 

1905. 


PROGRESS 


...IN... 


Alkaloidal  Chemistry 


WRING  THE  YEAR  1904. 


...BY... 


H.  M.  GORDIN. 
UNIVERSITY 


°F 


MILWAUKEE, 

Pharmaceutical  Review  Publishing  Co. 

1903. 


GENERAL 


Progress  in  Alkaloidal  Chemistry  During  the  Year  1904. 


By  H.  M.  Gordin. 


The  chemistry  of  alkaloids  has  received  many  valuable  contribu- 
tions during  the  year  of  1904.  While  the  year's  work  cannot  show 
such  important  syntheses  as  those  of  atropine  and  nicotine, 
accomplished  during  the  proceeding  year,  many  investigations  of 
great  importance  fall  to  the  credit  of  last  year.  The  constitution  of 
some  alkaloids,  for  example,  that  of  ricinine,  has  been  completely 
established.  The  researches  of  Knorr  and  others  upon  the  constitu- 
tion of  morphine  are  bringing  this  important  problem  very  near  to 
its  solution.  The  relations  between  the  other  opium  alkaloids  and 
the  constitution  of  some  of  them,  e.  g.,  apomorphine  are  also  being 
cleared  up.  The  constitution  of  conhydrine  and  of  the  different 
coniceines  also  promises  to  be  very  soon  worked  out.  The  identity 
of  lupinidine  with  sparteine  was  shown  by  Willstadter  and  his  colla- 
borators. Papaverine  and  cotarnine  received  a  great  deal  of  atten- 
tion last  year  and  many  interesting  derivatives  of  these  bases  were 
prepared  by  various  investigators.  New  color  reactions  for  the  in- 
dentification  of  some  alkaloids  were  discovered  by  Reichard  and 
others  and  the  presence  or  absence  of  certain  alkaloids  in  certain 
plants  was  also  definitely  established.  Only  one  new  alkaloid,  skim- 
mianine,  was  discovered  during  1904. 

I  shall  now  take  up  in  alphabetical  order  all  those  alkaloids  the 
chemistry  of  which  was  investigated  during  1904  beginning  with  two 
investigations  on  some  general  prpperties  of  the  vegetable  bases. 

Alkaloids.  Their  influence  upon  certain  reactions  of  oxidation. 
K.  Feder  has  investigated  the  influence  exerted  by  alkaloids  upon 
certain  reactions  of  oxidation.  Schlagdenhaufen  and  Schaer  had 
already  shown  that  while  an  aqueous  solution  of  mercuric  chloride 
had  no  effect  whatever  upon  tincture  of  guaiac,  the  addition  of  even 
a  trace  of  a  free  alkaloid  to  the  mixture  of  the  tincture  and  the 
mercury  salt  produces  a  blue  color.  In  the  present  investigation  it 
is  shown  that  most  alkaloids  are  capable  of  inducing  oxidations  in 
mixtures  of  cupric,  ferric,  mercuric,  silver,  gold  and  platinum  salts 

154434 


with  many  oxidizable  substances,  like  pyrogallol,  tincture  of  guajac, 
aloin,  pyrocatechin,  hydroquinone  and  orcin,  —  all  of  which  in  the 
absence  of  alkaloids  are  either  not  affected  at  all  or  affected  only 
very  slightly  by  the  above  mentioned  salts. 

On  the  other  hand  the  influence  of  alkaloids  upon  the  oxidation 
of  glucose  by  copper  and  mercury  salts  is  only  very  slight. 

The  same  is  true  with  regard  to  the  biuret  reaction  of  albu- 
menoids. 

In  the  course  of  this  investigation  it  was  found  that  the  unfavor- 
able influence  which  the  presence  of  glucose  exerts  upon  the  biuret 
reaction  can  be  eliminated  by  the  addition  of  a  little  hydrogen  per- 
oxide. Arch.  d.  Pharm.,  1904,  p.  680. 

Ammonium  bases  of  alkaloids.  M.  Scholtz  and  K.  Bode 
find  that  on  combining  the  various  N-alkyl  coniines  or  N-alkyl  con- 
hydrines  with  alkylhalides  there  are  always  formed  two  optical 
isomers  when  the  five  radicles  attached  to  the  nitrogen  atoms  are 
different  from  each  other.  These  isomers  differ  from  each  other  not 
only  in  direction  and  magnitude  of  rotation  but  also  in  solubility, 
melting  point  etc.  This  is  as  it  ought  to  be  expected.  Coniine  and 
conhydrine  both  containing  assy  metric  carbon  atoms  are  themselves 
optically  active.  When  the  nitrogen  atoms  of  these  bases  through 
the  addition  of  five  different  groups  also  become  assy  metric  there 
ought  to  be  formed  in  each  case  two  compounds  in  which,  to  one 
and  the  same  function  of  the  assymetric  carbon  atom,  there  ought 
to  be  an  addition  of  the  dextro  effect  of  the  now  assymetric  nitrogen 
atom  in  one  case  and  of  the  laevo  effect  in  the  other  case.  With  +  C, 
for  example,  we  ought  to  get  the  following  two  compounds: 

+  C  and  -f  C 
+  N  -N 

Such  compounds  are.  therefore,  not  optical  antipodes  which  differ 
from  each  other  only  in  the  direction,  or  in  the  absolute  magnitude 
of  rotation,  but  really  optically  different  substances '  in  which  both 
the  sense  and  the  absolute  magnitude  of  rotation  ought  to  be 
different.  Such  isomeric  compounds  generally  have  different  melting 
points,  different  solubilities  etc. 

As  most  alkaloids  containing  assymetric  carbon  atoms  are  optic- 
ally active  it  ought  to  be  possible  to  obtain  from  each  of  them  two 
optical  isomers  which,  like  those  obtained  from  coniine  and  conhy- 
drine, would  differ  from  each  other  in  several  physical  properties, 


when  their  nitrogen  atoms  are  made  assymetric.  But  on  making 
experiments  with  strychnine,  brucine,  nicotine,  tropine,  atropine  and 
cinchonine  it  was  found  that  no  such  optical  isomers  were  formed. 

It  would  seem,  therefore,  that  the  presence  of  the  propyl  group 
in  coniine  and  of  the  oxypropyl  group  in  conhydrine  is  particularly 
favorable  to  the  formation  of  the  above  mentioned  kind  of  isomerism. 
The  alkyl  derivatives  tried  in  this  investigation  were :  benzylbromide, 
methyliodo-acetate  and  benzyl-iodide.  Arch.  d.  Pharm.,  1904,  p.  568. 

Atropine.  C.  Reichard  finds  that  on  warming  a  mixture  of 
atropine  sulphate  and  mercurous  nitrate  with  a  few  drops  of  water 
double  decomposition  takes  place  at  first  with  the  formation  of  the 
difficultly  soluble  mercurous  sulphate.  On  further  heating  the  mix- 
ture becomes  black  from  the  reduction  of  the  mercury  salt  and  an 
agreeable  odor  is  developed  due  to  the  action  of  the  liberated  sul- 
phuric acid  on  the  atropine. 

With  silver  nitrate,  platinum  tetrachloride  or  palladium  chloride 
the  same  reaction  takes  place  but  is  not  as  sharp  as  with  the  mer- 
curous nitrate. 

On  adding  some  sulphuric  acid  and  bismuth  chloride  to  a  strong 
solution  of  atropine  sulphate  a  yellow  color  is  developed  which  dis- 
appears on  standing  or  upon  addition  of  water. 

With  sodium  nitroprusside  atropine  behaves  like  cocaine  (Chem. 
Ztg.  28,  p.  299)  with  this  difference  that  in  the  case  of  atropine  an 
aromatic  odor  is  developed  which  does  not  take  place  with  cocaine. 
Atropine  also  differs  from  cocaine  in  that  the  former  does  not  give 
any  color  reaction  with  titanic  acid  and  sulphuric  acid  (loc.  cit.). 

On  adding  some  hydrochloric  acid  to  a  mixture  of  atropine  sul- 
phate and  sugar  the  mixture  assumes  a  rose  red  color.  With  very 
small  amounts  of  the  alkaloid  the  color  disappears  after  a  while  but 
reappears  again  on  the  application  of  heat.  Alkalies  change  the 
color  to  green. 

Arsenates  and  arsenites  are  reduced  by  atropine  slowly  in  the 
cold,  quickly  on  application  of  heat. 

With  antimony  trichloride  atropine  gives  a  green  color  which  is 
not  changed  by  stannous  chloride.  (Morphine  is  colored  red  by  the 
same  reagent.) 

Warmed  with  a  very  dilute  solution  of  cobaltous  nitrate  atropine 
sulphate  gives  a  green  color  which  is  destroyed  by  ammonia.  A 
drop  of  strong  sodium  hydroxide  changes  the  color  to  violet. 


With  cobalt  sulphate  atropine  produces  an  aromatic  odor  but 
gives  no  color  reaction.  Chem.  Ztg.,  28,  p.  1048. 

Berberine.  M.  Freund  and  H.  Beck  have  prepared  some  alkyi 
derivatives  of  dihydroberberine  by  means  of  Grignard's  reaction. 

It  has  been  shown  in  a  previous  paper  that  cotarnine  forms  alkyl 
derivatives  of  hydro-cotarnine  when  subjected  to  Grignard's  re- 
action. The  reaction  with  cotarnine  takes  place  according  to  the 
following  scheme: 

CH2  CH2 

•   -v      /\       /\  /\       /\ 

O/  \CH2  O/  \CH2 

CH<  CH< 

0\        /\  NH.CHs >  0\        /\  NH.CHs       > 

\/        \CH  \/        \CH 

CHs.O  I!  CHs.O          /\ 

O  R/        \O.  Mg.  Halog. 

Cotarnine. 


CH2(^ 


CH2  CH2 

/N  /\  /\  /\ 

O/        \/        \CH2  O/        \/        \CH2 

CH2(    I 

O\        /\          NH.CHs >  O\        /\        /N.CHs 

\/        \  \/        \/ 

CHs.O  CH.OH  CHs.O  CH 


R-hydrocotarnine. 

As  according  to  Gadamer  (Chem.  Ztg.  1902,  291)  the  constitution 
of  berberinal  is  similar  to  that  of  cotarnine,  berberinal  ought  to  re- 
act with  Grignard's  reagent  in  the  same  way  as  cotarnine.  Experi- 
ments showed  that  such  is  really  the  case.  The  reaction  in  the  case 
of  berberinal  goes  according  to  the  same  scheme  as  with  cotarnine: 

CH2 


CH3.O 

/\ 
CH3.0/ 


\ 


O 
X\ 

/ 

/ 
1 

\0/ 

x\      / 

1 
^\ 

/      \/      \x 

N|H 

\           \ 

x                           > 

c 

/ 

H2 

CH 

ii 

\/ 

CH2 

II 
0 

Berberinal. 

o 
/\ 


CHs.O 

/\       /\       /\ 
CH3.0/        \/        \/ 

I  I 


\ox 

I 

I 


N 


H 


/\  \        / 

\  \/ 

CH         CH2 
/\ 
R     O.  Mg.  Halog. 


CHS 


CH2 > 


_CH2 


X\ 


\0/ 

I 


CHa.O 

/\        /\        /\ 
CHs.O/       NX       \/       \/ 

I  I 

\        /\       /\        /CH2 
\/       \/  N  \/ 
C  CH2 

\H.R 

R-Dihydroberberine. 


These    compounds    being    derivatives     of    dihydroberberine    are 
named  a-R-dihydroberberines. 


__  CH2 

" 


O 

/\ 
\o/ 


CH3.0 

x^\ 


/\      /\ 

/        \/  N  \/ 
C  CHj 


|CH2 


H2 
/ 

Dihydroberberine. 

These  a-alkyldihydroberberines  can  also  be  prepared  by  treating 
berberine  salts  with  Grignard's  reagent,  for  example  berberine  hydro- 
chloride  or  berberine  cyanide. 


0_        _CH2 
X\  / 

X         \  OX 


CHg.O 

/\       /\       x\ 

CH3.OX 


+  R.  Mo-.  I 

|CH2 


\/        Vf   N  \/ 
C      I      CH2 


C 
H 

Cl 


n 

Berberinehydrochloride. 

O CH2 

X\  X 

/      \ox 

II 

CH3.O 

/  \         /  \         /\        / 
CH3.OX        \/        \X 

+  Cl.  Mg.  I 
|CH2 
\       x\       x\       > 

\/         \X   N  \X 
C  CH 

I 
R 

a-R-dihydroberberine. 

These  dihydroberberine  bases  are  nearly  related  to  corydaline. 
They  are  yellow  crystalline  substances  and  form  crystalline  salts. 
The  solutions  of  these  salts,  unlike  those  of  berberine  salts,  are 
precipitated  by  ammonia  and  sodium  carbonate. 

Experimental:  —  a-Benzyldihydroberberine  was  prepared  by 
heating  either  berberinal,  berberine  hydrochloride  or  berberine 
cyanide  with  benzylmagnesium  chloride.  The  best  yield  is  obtained 
from  the  hydrochloride.  The  a-benzyl  compound  crystallizes  in 
lemon  yellow  crystals  and  forms  a  crystalline  hydrochloride  which 
is  perfectly  stable  in  the  air  when  perfectly  pure.  In  presence  of  im- 
purities the  hydrochloride  is  decomposed  on  standing  and  develops 
the  odor  of  benzoic  aldehyde  when  dissolved  in  water. 

When  heated  with  methyliodide  to  100°  «-benzyldihydroberberine 
forms  an  iodomethylate,  CosHssCUNI.  It  is  a  crystalline  powder 
difficultly  soluble  in  alcohol. 


tf-Methyldihydroberberine,  C^iEbiC^N,  was  prepared  from  ber- 
berine  hydrochloride  and  methylmagnesiumiodide.  It  forms  a  hydro- 
bromide  and  a  hydriodide.  The  hydrobromide  is  much  less  stable 
than  the  hydriodide  becoming  dark  brown  on  standing. 

a-Phenyldihydroberberine,  C26H2s04N,  was  prepared  from  ber- 
berine  hydrochloride  and  phenylmagnesium  bromide.  It  forms  a 
hydrobromide  which  is  very  difficultly  soluble  in  water.  From  it 
solutions  in  a  mixture  of  alcohol  and  glacial  acetic  acid  the  free  base 
is  precipitated  by  ammonia  in  yellowish  brown  crystals. 

Ber.   dtsch.  chem.  Ges.,  1904,  p.  4673. 

Brucine.  C.  Minunni  and  R.  Ciusa  have  investigated  the  action 
of  chlorine  upon  brucine.  On  passing  chlorine  into  a  solution  of 
brucine  in  glacial  acetic  acid  the  liquid  at  first  becomes  yellow,  after 
a  while  it  assumes  an  intensively  red  color  and  at  last  again  becomes 
yellow.  Addition  of  water  throws  down  a  white  crystalline  powder 
which  was  found  to  be  the  hydrochloride  of  hexachlorbrucine, 


The  hydrochloride  when  heated  becomes  brown  at  120°  and 
darkens  at  200°  but  does  not  melt  even  at  260°.  It  is  insoluble  in 
water,  ether  or  ligroin,  little  soluble  in  benzol  or  chloroform  and 
very  easily  soluble  in  alcohol,  acetic  ether  or  methyl  alcohol.  It  is 
also  soluble  in  potassium  hydroxide  and  ammonia.  On  exposure  to 
light  it  assumes  a  rose  red  color.  It  dissolves  in  sulphuric  acid  with 
evolution  of  hydrochloric  acid.  Strong  nitric  acid  does  riot  color  the 
salt.  It  is  physiologically  inactive. 

The  free  hexachlorbrucine  was  liberated  from  the  hydrochloride 
by  adding  a  saturated  solution  of  sodium  acetate  to  the  alcoholic 
solution  of  the  salt.  The  free  base  forms  a  white  powder  which  be- 
comes yellow  on  exposure  to  light,  is  soluble  in  most  organic  solvents 
and  insoluble  in  water  or  ligroin. 

Gazz.  Chim.  Ital.,  1904,  11,  p.  860. 

C.  Reichard  finds  that  when  one  drop  of  a  solution  of  bismuth 
chloride  is  mixed  with  some  solid  brucine  or  with  a  drop  of  a  con- 
centrated solution  of  brucine  a  beautiful  red  color  is  developed.  On 
now  adding  one  drop  of  hydrochloric  acid  and  evaporating  to  dry- 
ness  the  color  becomes  more  intensely  red  and  does  not  change  to 
yellow  as  is  the  case  with  the  red  color  obtained  from  brucine  and 
nitric  acid.  For  the  success  of  the  reaction  it  is  necessary  that  the 
brucine  be  always  in  excess. 


If  bismuth  subnitrate  be  used  in  the  reaction  instead  of  the 
chloride  there  is  no  color  even  on  warming  the  mixture  but  the 
addition  of  hydrochloric  acid  to  the  mixture  produces  the  red  color. 

Arsenic  and  tin  salts  do  not  give  any  color  reactions  with  brucine. 
Antimony  trichloride  produces  the  red  color  only  on  application  of 
heat.  Mercurous  salts  do  not  react  at  all  with  brucine.  Mercuric 
salts  react  only  in  the  heat. 

The  presense  of  cadmium,  copper  and  lead  do  not  interfere  with 
the  reaction  of  brucine  with  bismuth  chloride. 

Chem.  Ztg.,  1904,  p.  1024. 

C.  Reichard  has  examined  Fliickiger's  reaction  for  brucine 
(Zeitschr.  f.  anal.  Chem.,  1876,  pp.  15  and  342)  and  found  that  in  the 
absence  of  free  nitric  acid  free  brucine  gives  no  color  with  mercurous 
nitrate  but  if  a  solution  of  mercurous  nitrate  to  which  some  brucine 
has  been  added,  be  kept  for  some  time,  there  is  a  reduction  of  the 
mercury  salt  to  metallic  mercury.  With  a  salt  of  brucine  in  dilute 
solution  mercurous  nitrate  gives  at  first  a  yellow  color  which  upon 
concentration  of  the  liquid  is  changed  to  a  carmine  red.  Addition  of 
water  to  this  red  liquid  brings  back  the  yellow  color.  On  prolonged 
standing  the  mercury  salt  is  reduced  by  the  salt  of  brucine  in  the 
same  way  as  by  the  free  alkaloid. 

With  mercuric  nitrate  neither  the  free  base  nor  its  salts  show 
any  reaction  in  the  cold,  but  on  evaporating  a  solution  containing 
mercuric  nitrate  and  some  brucine  a  color  is  produced  which  is 
brown-red  in  artificial  light  and  violet  with  a  yellow  contour  in  day- 
light. Addition  of  stannous  chloride  to  this  colored  residue  produces 
a  white  curdy  precipitate. 

Silver  nitrate  is  quickly  reduced  by  brucine.  On  rubbing  together 
free  brucine  with  some  silver  nitrate  and  then  moistening  the  mixture 
with  water  black  metallic  silver  soon  separates  out  even  in  the  cold. 
Application  of  heat  makes  the  reaction  more  delicate.  When  a 
solution  of  a  brucine  salt  is  mixed  with  a  solution  of  silver  nitrate 
the  liquid  is  at  first  colorless  but  very  soon  a  deposit  in  the  form 
of  a  black  powder  makes  its  appearance.  On  evaporating  the  liquid 
a  varnish-like  coating  is  obtained  together  with  the  black  powder. 
This  coating  is  colored  deep  red  by  stannous  chloride.  The  red  color 
produced  by  the  stannous  chloride  cannot  be  ascribed  to  the  action 
of  the  nitric  acid  which  comes  from  the  silver  nitrate  for  the  reason 
that  no  color  is  produced  by  the  silver  nitrate  before  the  addition 


of  the  stannous  chloride.  Besides,  the  red  color  produced  by  nitric 
acid  in  solutions  6f  brucine  is  changed  to  violet  by  stannous  chloride. 
This  red  color  produced  by  the  stannous  chloride  does  not  disappear 
upon  the  addition  of  water  and  the  presence  of  an  excess  of  hydro- 
chloric acid  does  not  interfere  with  the  reaction. 

Silver  nitrite  behaves  with  brucine  exactly  like  silver  nitrate. 

On  evaporating  a  solution  of  copper  nitrate  with  some  brucine 
a  violet  blue  color  is  produced  which  gradually  changes  to  dark  blue. 
Addition  of  stannous  chloride  to  this  colored  residue  changes  the 
color  first  to  red,  then  to  brownish-red  and  at  last  to  brownish- 
yellow.  On  now  applying  heat  the  color  is  changed  to  deep  violet. 

When  brucine  or  its  sulphate  is  rubbed  up  with  a  drop  of  a  ten 
per  cent  solution  of  formic  aldehyde  and  the  moist  mixture  evapor- 
ated to  dryness  a  white  residue  is  left  which  becomes  light  blue  when 
touched  with  a  drop  of  a  solution  of  stannous  chloride.  The  reaction 
takes  place  even  in  the  cold.  Application  of  heat  changes  the  color 
to  y«llowish-green.  Strychnine  does  not  give  this  color  reaction. 

Chem.  Ztg.,-  1904,  pp.  912. 

Cevadine.  M.  Freund  finds  that  it  is  possible  to  introduce 
only  one  benzoyl  or  acetyl  group  into  cevadine  whereas  into  cevine 
two  such  groups  can  be  introduced.  The  relation  between  these  two 
alkaloids  can  therefore  be  expressed  as  foliows: 


Cevadine  Cevine 


P    w     MA  /O.acyl  n    TT    Mr*  /O.acvl 

C27H4lN06\O.C5H70  C27H4lNOe\0.acyl 

Monoacylcevadine.  Diacylcevine. 

It  was  further  found  that  hydrogen  peroxide  oxidizes  cevine  very 
quickly  to  a  substance  having  the  formula  C27H43N09.  As  this  sub- 
stance can  be  easily  reduced  back  to  cevine  by  means  of  sulphur 
dioxide  it  must  belong  to  the  group  of  amino  oxides,  Rs-NiO,  and 
can,  therefore,  be  named  cevine  oxide.  As  the  oxidation  of  cevine 
by  hydrogen  peroxide  takes  place  almost  immediately  and  the  cevine 
oxide  crystallizes  well  and  has  a  sharp  melting  point,  the  reaction 


10 

can  be  used  for  the  identification  of  cevine  which  crystallizes  witli 
difficulty  and  has  no  sharp  melting  point. 

From  the  formation  of  cevine  oxide  some  conclusions  can  be 
drawn  with  regard  to  the  function  of  the  nitrogen  atom  in  cevine. 
As  only  certain  tertiary  bases  are  capable  of  forming  amino  oxides 
the  nitrogen  in  this  alkaloid  must  be  tertiary.  This  has  already 
been  shown  previously  by  the  formation  of  cevine  iodomethylate. 
As  pyridine  does  not  form  such  an  amino  oxide  it  is  reasonable  to 
suppose  that  quinoline  and  isoquinoline  being  derivatives  of  pyridine 
are  also  incapable  of  forming  amino  oxides;  hence  the  nitrogen  atom 
in  cevine  cannot  belong  to  a  pyridine  complex.  The  bases  that  are 
capable  of  being  easily  converted  into  amino  oxides  all  belong  to  the 
type  R2:N.CH3,  e.  g.,  trimethylamine,  N-alkylpiperidenes,  N-alkyl- 
pyrrolidines  and  dimethylaniline.  As  experiment  had  shown  the 
absence  of  a  =N.CHs  group  in  cevine  it  must  be  supposed  that  the 
nitrogen  atom  in  this  alkaloid  and  in  cevadine,  like  the  nitrogen 
atom  of  hydroberberine,  belongs  to  a  double  ring  system. 

Experimental:  — The  monobenzoyl  cevadine  was  made  by 
heating  cevadine  with  benzoic  anhydride  to  about  106°  for  3  hours. 
The  benzoate  of  benzoyl  cevadine  formed  in  the  reaction  is  very 
difficultly  soluble  in  water,  a  little  more  soluble  in  ether  and  very 
easily  soluble  in  alcohol,  acetone  or  benzol.  It  contains  one  molecule 
of  water  of  crystallization  which  is  not  removed  even  at  120°. 

From  this  benzoate  the  free  benzoyl  cevadine  was  liberated  by 
ammonia  and  purified  by  dissolving  it  in  warm  alcohol  containing 
a  little  glacial  acetic  acid  and  reprecipitating  it  with  ammonia. 

On  warming  the  benzoyl  cevadine  with  acetic  anhydride  it  went 
into  solution  without  becoming  acetylized. 

For  the  estimation  of  the  benzoyl  groups  the  benzoyl  cevadine 
was  saponified  by  means  of  alcoholic  potassium  hydroxide,  the  alco- 
hol distilled  off  and,  after  adding  sulphuric  acid,  the  benzoic  and 
tiglic  acids  driven  over  with  steam  and  titrated  with  standard  alkali. 
When  pure  cevadine  is  saponified  a  molecule  of  tiglic  acid  is  split  off 
quantitatively. 

The  benzoyl  cevadine  forms  a  hydrochloride  which  can  be  obtained 
by  warming  benzoyl  cevadine  with  hydrochloric  acid  and  water.  The 
hydrochloride  contains  one  molecule  of  water  of  crystallization. 

A  Imlriodide  of  benzoyl  cevadine  can  be  prepared  either  by  treat- 


11 

ing  the  solution  of  the  hydrochloride  with  potassium  iodide  or  by 
rubbing  up  benzoyl  cevadine  with  hydriodic  acid. 

A  nitrate  of  benzoyl  cevadine  can  be  obtained  by  rubbing  up 
benzoyl  cevadine  with  nitric  acid. 

Acetyl  cevadine  was  made  by  boiling  for  a  few  minutes  cevadine 
with  acetic  anhydride  and,  after  adding  excess  of  ammonia,  shaking 
out  the  liquid  witli  ether.  The  acetyl  cevadine  when  heated  melts 
at  first  at  182°,  then  becomes  solid  on  further  heating  and  melts 
again  at  234°.  The  acetyl  cevadine  was  converted  into  a  hydro- 
chloride  by  adding  hydrochloric  acid  to  its  alcoholic  solution  and 
evaporating  the  liquid  to  dryness  in  vacuum. 

Dibenzoyl  cevine  was  prepared  by  the  same  method  described 
above  for  the  preparation  of  benzoyl  cevadine. 

The  estimation  of  the  benzoyl  groups  was  made  by  saponifying 
the  dibenzoyl  cevine  with  alcoholic  potassium  hydroxide  and,  after 
making  the  liquid  acid,  extracting  and  weighing  the  benzoic  acid. 

A  hydrochloride  of  dibenzoyl  cevine  was  obtained  by  rubbing  up 
the  benzoate  of  dibenzoyl  cevine  with  hydrochloric  acid  and  removing 
the  benzoic  acid  with  ether.  A  difficultly  soluble  nitrate  and  an  ace- 
tate of  dibenzoyl  cevine  were  also  prepared. 

Diacetyl  cevine  was  obtained  in  the  same  waj  as  the  monoacetyl 
cevadine. 

Cevine  oxide  was  prepared  by  gently  warming  cevine  with  double 
its  amount  of  hydrogen  peroxide  (30%)  for  about  twenty  minutes 
and  recrystallizing  the  product  from  diluted  alcohol.  The  estimation 
of  nitrogen  in  the  cevine  oxide  had  to  be  carried  out  by  Kjeldahl's 
method  as  Dumas'  method  gave  too  high  results.  A  hydrochloride 
and  a  chloraurate  of  cevine  oxide  where  also  prepared. 

On  adding  ammonia  to  a  solution  of  hydrochloride  of  cevine  oxide 
the  liquid  remains  clear  in  the  cold  but  on  warming  the  solution  the 
free  cevine  oxide  crystallizes  out. 

When  a  current  of  sulphur  dioxide  is  passed  into  a  chloroformic 
solution  of  cevine  oxide  a  double  compound  is  formed  according  to 
following  equation: 

/O 
C27H4308 !  N:0  +  S02  =  C27H43O8  i  N<     | 

\S02 

When  this  double  compound  is  dissolved  in  water  it  is  decom- 
posed "into  cevine  and  sulphuric  acid  which  can  be  removed  by  barium 
chloride.  The  reaction  takes  place  according  to  following  equation : 


12 
/O 


C27H4308  1  N<     |      +  H20  =  C27H4308  i  X  + 
\S02 


The  cevine  set  free  in  this  reaction  was  identified  after  extracting 
it  from  the  liquid  by  chloroform  in  presence  of  sodium  carbonate,  by 
its  potassium  salt  and  by  converting  it  again  into  cevine  oxide. 

Ber.  Dtsch.  chem.  Ges.,  1904,  p.  1946. 

Cinchona  Alkaloids.  A.  Christensen  continues  his  investig- 
ations of  the  bromine  derivatives  of  the  cinchona  alkaloids. 

Cinchonidine  dibromide,  Ci9H220N2Bi*2,  was  prepared  by  the  same 
method  as  cinchonine  dibromide.  (See  Progress  in  Alkaloidal  Chem- 
istry during  1903,  this  Review  1904.) 

The  author  finds  that  the  compound  made  by  Skalweit  (Ann. 
Chenr.  Phar.,  172,  p.  102)  and  named  by  him  dibromcinchonidine  sup- 
posing it  to  be  a  substitution  product  of  cinchonidine  is  identical 
with  cinchonidine  dibromide  and  that  the  dioxycinchonidine  of  Skal- 
weit does  not  exist. 

The  author  has  also  repeated  the  experiments  of  Galimard  (Ball. 
Soc.  Chim.  [3]  25,  p.  84)  on  «  and  p  dibromcinchonidine  and  found 
that  these  compounds  too  were  not  substitution  products  but 
addition  products. 

Monobromcinchonidine,  Ci9H2iBrON2,  was  made  by  boiling  the 
cinchonidine  dibromide  with  twenty  parts  of  alcohol  and  then  adding 
half  a  part  potassium  hydroxide  dissolved  in  alcohol.  The  mono- 
bromcinchonidine  crystallizes  in  microscopic  needles  free  from  water 
of  crystallization,  turns  the  plane  of  polarization  to  the  left  and  is 
insoluble  in  water  but  soluble  in  ether  or  alcohol.  It  forms  an  oxal- 
ate  and  a  hydrobromide,  Ci9H2iBrON2.2HBr  +  2H20.  Attempts  to 
make  a  hydrobromide  containing  only  one  molecule  of  hydrobromic 
acid  were  not  successful. 

Dehydrocinchonidine  was  prepared  by  boiling  cinchonidine  dibro- 
mide with  ten  parts  of  alcohol  and  one  part  potassium  hydroxide 
for  twenty  hours  and  then  passing  into  the  liquid  a  current  of  carbon 
dioxide.  The  dehydrocinchonidine  forms  a  crystalline  powder  melting 
at  194°  and  corresponds  to  the  formula  Ci9H2oON2.  It  is  easily 
soluble  in  chloroform  but  difficultly  soluble  in  alcohol. 

Dibromcinchonidine  hydrobromide  perbromide  Ci9H2oBr20N2  . 
2HBr.  Br2,  was  prepared  by  heating  a  solution  of  dihydrocinchonidine 
in  glacial  acetic  acid  containing  hydrobromic  acid  and  bromine. 


18 

The  perbromide  is  insoluble  in  ether,  difficultly  soluble  in  glacial  acetic 
acid  and,  unlike  the  perbromide  of  cinchonidine  dibromide,  does  not 
loose  bromine  on  exposure  to  the  air. 

Dibromcinchonidine,  Ci9H2oBr20N2,  was  prepared  from  the  above 
perbromide  by  reducing  the  latter  with  sulphurous  acid  and  precipi- 
tating the  brominated  base  with  ammonia.  The  dibromcinchonidine 
is  extremely  easily  soluble  in  alcohol  but  can  be  recrystallized  from 
a  mixture  of  alcohol  and  chloroform. 

Quinine  dibromide,  C2oH2402N2Br2,  is  best  prepared  by  a  method 
similar  to  that  of  preparing  cinchonine  dibromide  (Journ.  pr.  Chem., 
63,  p.  334 ;  68.  p.  428).  Ordinary  (not  anhydrous)  quinine  is  dissolved 
in  glacial  acetic  acid  containing  the  theoretical  amount  of  hydro- 
bromic  acid  and  to  the  solution  is  added  the  theoretical  amount  of 
bromine.  After  diluting  the  liquid  with  a  little  water  a  considerable 
excess  of  ammonium  nitrate  is  added  to  the  solution.  The  nitrate 
of  quinine  dibromide  soon  separates  out  and  the  free  base  can  be 
liberated  from  the  nitrate  by  means  of  ammonia. 

By  treating  the  quinine  dibromide  with  silver  nitrate  or  by  pro- 
longed boiling  of  the  dibromide  with  lead  acetate  it  is  possible  to 
remove  one  molecule  of  hydrobromic  acid  from  the  compound,  but 
the  resulting  monobromquinine  seems  to  undergo  some  change  by 
this  treatment  as  the  free  alkaloid  thus  obtained  does  not  form  any 
crystalline  salts  with  acids. 

Monobromquinine,  C2oH23Br02N2,  can  be  obtained  by  treating 
an  alcoholic  solution  of  quinine  dibromide  with  an  excess  of  alcoholic 
potassium  hydroxide  in  the  cold.  The  monobromquinine  melts  at 
210°,  is  difficultly  soluble  in  alcohol,  has  the  specific  rotation  —118.1°, 
gives  the  thalleioquin  reaction  and  forms  fluorescent  solutions.  A 
hydrochloride  of  monobromquinine  crystallizing  with  various  amounts 
of  water  of  crystallization,  a  hydrobromide  crystallizing  both  with 
and  without  water  of  crystallization,  a  sulphate  and  an  iodosulphate 
were  also  obtained. 

Dehydroquinine,  C2oH2202N2,  was  prepared  by  heating  quinine 
dibromide  with  five  parts  alcohol  and  half  ja,  part  of  potassium 
hydroxide  for  twenty  hours  and  then  passing  into  the  liquid  a  current 
of  carbon  dioxide. 

The  dehvdroquinine  was  purified  by  converting  it  into  the  oxalate 
and  setting  the  base  free  by  ammonia.  It  gives  the  thalleioquin 


14 

reaction    and    forms   fluorescent  solutions.     A  hydrochloride  and  a 
herapathite  of  the  dehydrobase  were  also  obtained. 

When  treated  with  bromine  dehydroquinine  seems  to  be  converted 
into  dibromquinine,  C2oH22Br2OaN2.  Journ.  pr.  Chem.,  69,  p.  193. 

Cinchonine.  P.  Kabe  and  W.  Denham  find  that  when  the 
iodomethylate  of  cinchonine  is  heated  in  acetic  acid  solution  hydriodic 
acid  is  eliminated  and  methyl  cinchotoxin  is  formed. 


CH2 CH CH.CH=CH2 


CH2 
CH2 


C9H6N.H2C.C(OH)— N- 


HI 


CH CH- — CH.CH=CH 

CH2 
CH2 


I      CH3 

Cinchonine  iodomethylate. 


CeH6N.CH2.CO        N CH2 

I 


CH3 
Methylcinchotoxin. 


This  transformation  in  acid  solution  is  similar  to  the  one  which 
takes  place  in  alkaline  solution  as  observed  by  previous  investigators 
(Glaus  and  Miller,  Ber.  Dtsch.  chem.  Ges.,  13,  p.  2293;  Freund  and 
Rosenstein,  Annal.  Chem.  Phar.,  277,  p.  279). 

Ber.  Dtsch.  chem.  Ges.,  1904,  p.  1(574. 

Zd.  H.  Skraup  and  R.  Zwerger  have  tried  to  establish  the 
structural  formulas  of  the  four  isomeric  bases:  cinchonine,  a-i-cin- 
chonine,  yS-i-cinchonine  and  allocinchonine.  In  a  previous  paper  it 
had  been  shown  that  it  is  possible  to  ascribe  to  these  isomeric  bases 
such  formulas  as  would  account  for  the  formation  of  one  and  the 
same  hydriodocinchonine  through  the  addition  of  hydriodic  acid  to 
any  of  them  ond  also  for  the  formation  of  ail  these  isomeric  bases 
from  this  hydriodocinchonine  when  hydriodic  acid  is  splitt  off  from  it. 


CH 

\ 


H 

/ 

\C— CH=CH2 
|CH2 


CH 
^\ 

\C=CH-CH3 

CH2 


15 

3 

CH 

H 

\2/  1 

|C— CHI— CH8 

4 


Hydriodociuchoniiie. 


CH 

K 

\CH-CH— CH3 


/CH 

/ 


It  can  be  seen  that  if  the  four  isomeric  cinchonine  bases  be  sup- 
posed to  correspond  respectively  to  1,  2,  3  and  4,  the  formation  of 
all  of  them  from  the  same  hydriodocinchonine  can  be  explained  by 
assuming  that  the  hydrogen  which  goes  out  together  with  the  iodine 
comes  from  a  different  one  of  the  numbered  carbon  atoms  of  the 
hydriodocinchonine  for  each  of  the  iso  bases. 

On  trying  to  verify  these  considerations  by  making  a  hydro- 
chlor  addition  product  of  a-i-cinchonine  and  then  splitting  off 
again  the  hydrochloric  acid,  it  was  found  that  in  the  action  of 
hydrochloric  acid  upon  a-i-cinchonine  the  chief  product  is  ordinary 
hydrochlor  cinchonine  and  that  only  a  small  amount  of  hydrochlor- 
a-i-cinchonine  is  formed  as  a  secondary  product.  It  was  also  found 
that  ordinary  hydrochlorcinchonine  is  partly  converted  into  hydro- 
chlor-a-i-cinchonine  when  the  former  is  heated  under  pressure  with 
concentrated  hydrochloric  'acid.  It  is  therefore  reasonable  to  assume 
that  the  little  hydrochlor-a-i-cinchonine  formed  in  the  first  reaction  is 
only  a  product  of  transformation  of  ordinary  hydrochlorcinchonine. 

It  was  further  found  that  on  splitting  off  hydrochloric  acid  by 
means  of  alkali  one  and  the  same  base,  namely,  cinchonine  was  ob- 
tained from  hydrochlorcinchonine  as  well  as  from  hydrochlor-a-i- 
cinchonine.  This  fact  can  of  course  not  be  explained  by  ascribing 
to  the  four  iso-bases  the  formulas  given  above  according  to  which 
we  ought  to  get  different  bases  from  different  hydrochlor  derivatives. 
But  as  hydrochlorcinchonine  is  under  certain  conditions  transformed 


16 


into  hydrochlor-<z-i-cinchonine  no  valid  conclusions  can  be  drawn 
from  the  products  of  the  reaction  with  alkali. 

On  subjecting  the  other  isomeric  cinchonines  to  the  action  of 
hydrochloric  acid  only  a  little  ordinary  hydrochlorcinchonine  was 
obtained  but  no  isomeric  addition  products  could  be  isolated. 

On  treating  the  three  isobases  of  cinchonine  with  chlorine  it  was 
found  that  a-  and  /^-i-cinchonine  did  not  react  at  all,  but,  that  allo- 
cinchonine,  like  cinchonine  itself,  took  up  one  molecule  of  chlorine 
giving  dichloride  of  allocinchonine  which  was  not  identical  with  cin- 
chonine dichloride.  Monatshefte  f.  Chem.,  1904,  p.  894. 

/3-i -Cinchonine.  K.  Kaas  finds  that  the  substance  obtained 
by  melting  the  sulphate  of  /3-i-cinchonine  (which  is  a  tertiary  base 
and  contains  an  OH  group)  is  a  seconda^  base  and  contains  a  CO 
group.  As  the  transformation  is  the  same  as  that  which  takes  place 
when  tertiary  cinchonine  containing  an  OH  group  is  changed  to 
secondary  cinchonicine  containing  a  CO  group,  the  substance  ob- 
tained by  melting  /?-i-cinchonine  sulphate  should  be  named  /5-i-cin- 
chonicine,  not  /S-i-pseudocinchonicine  as  had  been  proposed. 

That  yj-i-cinchoninicine  is.  really  a  secondary  base  was  shown  by 
the  formation  of  the  hydriodide  of  N-methyl  /3-i-cinchonicine  when  the 
base  is  treated  with  methyl  iodide.  The  presence  of  a  CHs  group 
linked  to  the  nitrogen  atom  in  the  methylated  base  was  shown  by 
Herzig  and  Meyer's  method  and  that  the  CHs  group  was  not  linked 
to  oxygen  was  shown  by  the  negative  results  obtained  by  Zeisel's 
method. 


CH2- 

CH2 

i 

CH2 

C9H6N.CH2.C(OH)-N- 
Cirichonine. 


•CH  —  CH2 


CH  =  CH2 


CH2 
CH2 

C0H6CH2.CO          NH CH2 

Cinchonicine. 


Another  anology  between  yg-i-cinchonicine  and  cinchonicine  was 
found  in  the  fact  that  when  the  iodomethylate  of  /2-i-cinchomne  is 
heated  with  potassium  hydroxide,  hydriodic  acid  is  eliminated  and 
the  resulting  compound  is  identical  with  the  one  obtained  by  methyl- 
ating  /?-i-cinchonicine.  In  exactly  the  same  way  the  iodomethylate 
of  cinchonine  when  heated  with  potassium  hydroxide  is  converted 
into  methylcinchonicine.  (See  page  123.) 


17 

An  attempt  to  prove  the  presence  of  a  CO  group  in  /3-i-cinchoni- 
cine  by  means  of  phosphorus  pentachloride  did  not  give  the  desired 
results:  only  one  chlorine  atom  entered  into  the  compound  instead 
of  two  as  should  be  expected  from  a  ketone.  As  there  was  evolution 
of  hydrochloric  acid  in  this  reaction  it  is  probable  that  at  first  the 
oxygen  atom  of  the  -CO  group  is  replaced  by  two  chlorine  atoms  but 
that  the  dichlorcompound  soon  looses  hydrochloric  acid  and  is  con- 
verted into  the  monochlorderivative. 

Monatshefte  f.  Chem.  1904,  1145. 

Cocaine.  C.  Reichard  gives  the  following  new  reactions  for  the 
detection  and  identification  of  cocaine. 

1.  If  to  a   rather  concentrated  cold  solution  of  a  cocaine  salt 
a  solution  of  sodium  nitroprusside  be   added    the   solution  becomes 
turbid  and,   with  the  aid  of  a  magnifying  glass,  small  crystals  of  a 
reddish  color  can  be  noticed  in  the  liquid.    Morphine  salts  do  not 
give  this  reaction. 

2.  If  to  a  quite  concentrated  solution  of  cocaine  hydrochloride 
a  strong  solution  of  uranium  nitrate  be  added  a  yellow  crystalline 
precipitate  is  formed  which  is  most  probably  a  double  salt  of  cocaine 
and  uranium. 

3.  If  some  titanic  acid  be  dissolved  in  warm  concentrated  sul- 
phuric acid  and  to  the  cooled  solution  be  added  some  cocaine  hydro- 
chloride  there  is  no  reaction  whatever  in  the  cold  even  on  prolonged 
standing.    But  if  the  mixture  be  warmed  in    a   porcelain    dish   till 
stripes  and  oily  drops  appear  on  the  sides  of  the  vessel  a  beautiful 
blue  or  violet  color  is  developed  which    is  very  stable.    On  adding 
water  to  the  liquid  a  blue  precipitate  settles  at  the  bottom  of  the 
vessel.    The  reaction  is  undoubtedly  due  to  the  reduction  of  titanic 
acid   by   the    methyl    alcohol    formed    in    the    saponification    of   the 
alkaloid  by  the  sulphuric  acid. 

4.  If  to  a  mixture  of  potassium  methylsulphate  and  sulphuric 
acid  a  little  cocaine  hydrochloride  be  added  and  the  mixture  warmed 
a  strong  peppermint  odor  is  developed  which    is    permanent  for  a 
long  time. 

5.  On  warming   cocaine  hydrochloride  with  a  mixture  of   urea 
and  sulphuric  acid  the  mixture  assumes  a  blue  color  which  becomes 
deeper  as  the  temperature  rises.    If  in  this  reaction  ethylene  diarnine 
be  substituted  for  urea  there  is  first  an  evolution  of   hydrochloric 
acid  but  on  applying  heat  the  blue  color  appears. 

Chem.  Ztg.,J1904,  p.  299. 


18 

C.  E.  Carlson  finds  that  in  testing  cocaine  hydrochloride  for  the 
presence  of  reducing  substances  (cinnamyl  cocaine)  by  means  of 
potassium  permanganate  and  sulphuric  acid  it  is  best  to  leave  out 
the  sulphuric  acid  altogether.  The  sulphuric  acid  seems  to  retard 
the  velocity  of  the  reaction  changing  in  some  way  the  reducing  sub- 
stance. It  was  also  found  that  if  the  sulphuric -acid  be  added  after 
the  potassium  permanganate  the  retardation  is  less  than  when  the 
order  is  reversed.  Pharm.  Centralhalle,  1904,  p.  69. 

Coffearine.  L.  Graf  corroborates  the  statement  of  P.  Paladino 
(Ber.  Dtsch.  Chem.  Ges.  1894,  406.  R.)  about  the  existence  in 
coffee  of  the  alkaloid  coffearine. 

That  this  alkaloid  is  not  formed  by  the  action  of  the  calcium 
oxide,  which  Paladino  used  in  his  method  of  extraction,  upon  coffeine 
was  shown  by  the  fact  that  no  coffearine  could  be  obtained  by  the 
author  from  coffeine  by  treating  it  with  calcium  oxide.  On  the  other 
hand  coffearine  was  obtained  from  aqueous  extracts  of  coffee  even 
without  the  use  of  calcium  oxide. 

The  formula  of  coffearine,  Ci^Hie^Oi,  established  by  Paladino 

was  found  to  be  correct. 

Zeitschr.  offentl.  Chem.,  1904,  p.  280. 

Conhydrine.  K.  Loffler  has  investigated  the  constitution  of 
conhydrine,  pseudoconhydrine  and  of  some  of  the  coniceines. 

As  both  conhydrine  and  pseudoconhydrine  give  the  same  a-pipe- 
colinic  acid  upon  oxidation  the  OH  group  in  both  these  bases  must 
be  situated  in  the  side  chain  (Willstatter,  Ber.  Dtsch.  Chem.  Ges.  34, 
3166). 

Of  the  three  theoretically  possible  oxypiperidines  containing  the 
OH  group  in  the  side  chain  one  was  prepared  synthetically  by  La- 
denburg  and  found  to  have  the  constitution  of  an  a-pipecolylmethyl- 
alkine 

CH2 
H2C/  \CH2 

H2C\       /CH— CH2-CH.OH-CH3 
NH 
a-Pipecolylmethylalkine. 

As  there  are  two  assymetric  carbon  atoms  in  this  compound  it 


19 

ought  to  exist  in  four  optically  active  modifications  and  two  racemic 
modifications.  Conhydrine  and  pseudoconhydrine  can  be  assumed  to 
be  two  of  the  four  optically  active  forms;  :the  synthetic  a-pipecolyl- 
methylalkine is  one  of  the  racemic  modifications  and  is  chemically 
identical  with  conhydrine. 

The  chemical  identity  of  conhydrine  with  a-pipecolylmethylalkine 
was  shown  by  the  following  experiments: 

1.  On  heating  the  synthetic  a-pipecolylmethylalkine  with  fuming 
hydrochloric  acid  to  220°  water  is  eliminated  and  two  isomeric  bases 
are  formed  which  are  very  similar  to  a-coniceine  and  /?-coniceine  re- 
spectively previously  obtained  from  conhydrine  by  the  same  method. 
The  salts  obtained  from  the  two  bases  were  also  found  to  be  almost 
identical  with  those  obtained  from  a-coniceine  and  #-coniceine  respec- 
tively. The  only  difference  between  a-coniceine  and  -coniceine  on  one 
hand  and  the  bases  obtained  from  a-pipecolylmethylalkine  on  the  other 
is  that  the  former  are  optically  active  while  the  latter  are  inactive. 
The  latter  must  therefore  be  assumed  to  be  the  racemic  forms  of 
a-coniceine  and  /?-conieeine  respectively. 

The  reaction  according  to  which  conhydrine  or  its  isomer  a-pipe- 
colylmethylalkine are  converted  into  coniceines  is  as  follows: 
CH2  CH2 


H2C/      \CH2  H2C/    \CH2 


H2C; 


/CH-CH2— CH.OH-CH3  ==  H2C\      /'CH-CH2        +H2O 
\/                                                              \/  | 

NH  >    N CH-CHs 

Conhydrine.  Coniceine. 

2.  On  heating  a-pipecolylmethylalkine  with  hydriodic  acid   and 
amorphous  phosphorus  two  isomeric  compounds  are  obtained  which 
contain  an    atom  of  iodine  instead  of  the  OH  group.    Both    these 
iodine  containing    bases  behave  exactly  like  the  iodine  derivatives 
obtained  from  conhydrine  by  the  same  method. 

3.  On  treating  the  iodine  compounds  obtained  from  the  a-pipe- 
colylmethylalkine with  sodium  hydrate,  hydriodic  acid  is  eliminated 
and  the  bases  thus  obtained  are  identical  with  e-coniceine  previously 
obtained  by  Lellmann  from  conhydrine  by  the  same  method,  i.  e., 
replacing  the  OH  group  by  iodine  and  then  splitting  off  hydriodic 
acid  by  means  of    alkali.    The    reaction    takes    place    according   to 
the  following  equation : 


20 
CH2  CH2 


H2C/    \CH 


H2C 


H2C\     /CH-CH2-CHI-CH3    =      H2C\      /'CH-CH2  +  HI 

NH  N—      _CH-CH3 

Jodoconiine.  £-Coniceine. 

The  only  difference  between  e-coniceirie  and  the  bases  obtained 
from  the  iodine  derivative  of  «-pipecolylmethylalkine  is  that  e-coni- 
ceine  is  optically  active  while  the  bases  from  a-pipecolylmethylalkine 
are  inactive.  We  can  again  assume  that  these  bases  are  the  two 
racemic  forms  of  e-coniceine. 

Attempts  to  split  up  synthetic  a-pipecolylmethylalkine  into  its 
active  components  and  thus  obtain  bases  in  every  respect  identical 
with  conhydrine  and  pseudoconhydrine  were  not  successful.  No 
crystalline  compounds  could  be  isolated. 

Ber.  Dtsch.  Chem.  Ges.,  1904,  p.  1879. 

Cotarnine.  J.  J.  Dobbie,  A.  Lauder  and  C.  K.  Tinkler  show 
that  the  changes  in  the  spectrum  of  cotarnine  produced  by  equivalent 
amounts  of  different  alkaline  hydroxides  and  by  ammonia  can  be 
utilized  for  establishing  the  relative  strengths  of  these  substances. 
As  had  been  shown  in  a  previous  paper  (See  this  Review,  1904,  Pro- 
gress in  Alkaloidal  Chemistry  during  1903)  cotarnine  exists  in  two 
forms:  a  carbinol  form  and  an  ammonium  hydroxide  form 

CH3.O  CH.OH  CH3.O  CH 

/\        /\  /\ 

O/        \/        \N.CH3  O/ 


CH2 


/   I  I 

\   I 


CH2 


|   \OH 


O\       S\       sCH2  \       /\       /CH2 

\/        \/  \/       \/ 

CH2  CH2 

Carbinol  form.  Ammoniumhydroxide  form. 

which  have  different  spectra  both  in  the  free  condition  and  as 
salts.  The  addition  of  alkali  to  a  solution  of  the  yellow  ammonium 
form  changes  the  cotarnine  to  the  colorless  carbinol  form.  On  using 
equivalent  amounts  of  different  alkaline  hydroxides  and  ammonia 
and  observing  the  changes  produced  in  the  spectra  it  was  found  that 


21 

the  relative  strengths  of  the  different  alkalies  are  the  same  as  found 
by  other  methods. 

The  action  of  sodiumhydroxide  on  an  aqueous  solution  of  cotar- 
nine  (containing  the  ammonium  form)  can  be  explained  by  assuming 
that  the  solution  contains  a  mixture  in  equilibrium  of  the  undis- 
sociated  ammonium  form  together  with  the  OH  and  the  other  ion 
resulting  from  its  dissociation,  with  practically  none  of  the  carbinol 
form.  By  the  addition  of  sodium  hydroxide  the  active  mass  of  the 
OH  ions  is  increased  and  the  dissociation  of  the  ammonium  form  is 
diminished.  The  ammonium  form  then  passes  into  the  carbinol 
form,  in  which  the  dissociation  is  at  a  minimum,  until  the 
equilibrium  is  restored.  The  further  addition  of  sodium  hydroxide 
leads  to  a  repetition  of  these  changes  until  the  ammonium  form  is 
practically  all  converted  into  the  carbinol  form. 

Journ.  Chem.  Soc.,  1904,  p.  121. 

According  to  C.  Liebermann  and  F.  Kropf  when  cotarnine  is 
shaken  with  acetone  in  presence  of  a  small  amount  of  a  saturated 
solution  of  sodium  carbonate  a  condensation  between  the  base  and 
the  acetone  takes  place  with  the  elimination  of  one  molecule  of  water. 
The  reaction  is  as  follows: 


(I) 


CHs.O  CHO 

/\        / 
O/        \/ 


0\        /\ 

\/        CH2.CH2.NH.CH3 


Cotarnine. 

CH^CH.CO.CHs 


O/ 

| 
I 

o\ 


prr  H20 

°H2\      I 

\/       \ 

CH2.CH2.NH.CH3 


Anhydrocotarnine  acetone. 

If  the  cotarnine  be  supposed  to  react  in  its  tautomeric  form  the 
equation  can  be  written  in  the  following  way  : 


22 


(II) 

CH3.O  CH OH 

/\        /\        / 
O/  \X.CH3 

CH2\|  +CH3.CO.CH3  = 


O\       /\ 

\/      v/ 

CH2 

Cotarnine  (tautomeric  form.) 


CH3.0  CH.CH2.CO.CH3 

/\        /\ 
O/  \X.CH3 

CH2(   |  +  H20 

O\        /\       /CH2 
\/        \/ 
CH2 

Anhydrocotarnine  acetone. 


A  similar  condensation  of  cotarnine  takes  place  with  other 
ketones  containing  a  CHs  group  and  also  with  such  substances  which, 
like  malonic  ester,  contain  a  CH2  group  between  carbonyl  groups. 

The  anhydrocotarnine  acetone  crystallizes  in  colorless  or  slightly 
yellowish  prisms  which  are  easily  soluble  in  alcohol,  acetone,  ether 
and  benzol  but  insoluble  in  excess  of  sodium  carbonate.  Melting 
point  83°. 

A  hydrochloride  of  anhydrocotarnine  acetone  was  obtained  by 
passing  hydrochloric  acid  gas  into  an  ethereal  solution  of  anhydro- 
cotarnine acetone  and  recrystallizing  the  salt  from  a  mixture  of 
alcohol  and  ether.  The  salt  melts  with  decomposition  at  171°. 

A  platinum  salt  of  anhydrocotarnine  acetone  was  also  obtained. 
The  platinum  salt  is  quite  soluble  in  water. 

On  digesting  anhydrocotarnine  with  methyliodide  at  ordinary 
temperature  anhydromethylcotarnine  acetone  iodomethylate  was 
obtained.  It  crystallizes  from  hot  water  in  small  colorless  plates 
melting  at  144°.  The  hydriodide  of  an  hydrocotarnine  acetone 
formed  in  the  reaction  being  more  soluble  than  the  quaternary  base 
was  removed  bv  cold  water. 


23 

CH3.0  CH  =  CH.CO.CH3 

/\        / 
O/ 

CH2(   | 

o\     /\ 

\/      \ 

CH2.CH2.N.(CH3)3.I 
Anhydromethyl  cotarnine  acetone  iodomethylate. 

On  converting  the  iodomethylate  by  means  of  silver  chloride  into 
the  corresponding  chloromethylate  and  treating  the  latter  with 
platinum  tetrachloride  the  corresponding  chloroplatinate  was  ob- 
tained. 

Anhydrocotarnine  methylpropyl  ketone,  Ci7H23N04,  was  pre- 
pared by  the  same  method  as  the  acetone  compound.  It  had  no 
sharp  melting  point. 

Anhydrocotarnine  acetophenone  was  prepared  in  the  same  way 
as  the  acetone  compound.  The  acetophenone  condensation  product 
is  easily  soluble  in  benzol  and  in  warm  alcohol.  It  crystallizes  in 
colorless  prisms  melting  at  126°  and  forms  a  yellowish  platinum 
salt. 

Anhydrocotarnine  malonic  ester  was  prepared  by  the  same 
method  as  the  other  condensation  compounds.  It  forms  crystals 
and  is  not  precipitated  by  sodium  carbonate  from  its  solutions  in 
acids.  Ber.  Dtsch.  Chem.  Ges.,  1904,  p.  211. 

C.  Liebermann  and  A.  Clawe  show  that  cotarnine  and  hydra- 
stinine  are  capable  of  forming  condensation  products  not  only  with 
methyl  ketones  and  other  compounds  containing  methylene  carbon 
atoms  between  carbonyl  groups  (see  preceeding  paragraph),  but 
with  a  great  many  other  compounds,  like  counmrone,  resorcin,  etc. 
On  the  other  hand  it  was  found  impossible  to  condense  the  two  bases 
with  meconin  and  in  this  way  convert  them  into  narcotine  and 
hydrastine  respectively. 

The  various  condensation  products  are  not  all  equally  stable. 
The  malonic  ester  compounds,  for  example,  are  so  easily  decomposed 
that  the  free  bases  are  liberated  even  in  the  simplest  reactions,  while 
some  of  the  other  condensation  products  are  not  decomposed  unless 
boiled  or  digested  for  some  time  with  strong  mineral  acids.  In  these 
decompositions  the  compounds  always  break  up  into  their  component 
parts. 


24 

As  a  condensing  agent  in  these  reactions  piperidine  was  frequently 
found  to  be  superior  to  sodium  carbonate. 

With  regard  to  the  structure  of  these  compounds  there  are  two 
formulas  to  be  considered: 

(I)  (II) 

CH^CKCO.  .  CH  -  CH2.CO.. 

\        /  \       /\ 

Ketone  residue  \N.CH3  Ketone  residue 

I  I 

/\  /\        /CH2 

/       \  /        \/ 

CH2.CH2.NH.CH3  CH2 

As  (I)  is  a  secondary  and  (II)  a  tertiary  base  experiments  were 
made  with  a  view  to  establish  the  constitution  by  making  alkyl  and 
acyl  derivatives  of  the  compounds.  (See  next  paragraph.)  It  was 
found  that  for  some  of  the  condensation  products  (I)  must  be 
accepted  while  for  others  (II)  is  preferable.  The  formulae  are,  there- 
fore, tautomeric. 

The  condensation  products  prepared  in  this  investigation  are  as 
follows  : 

Anhydrocotarnine  phenylacetic  ester, 

/C6H5 
CH:C 

C6H(:02:CH2)(O.CH3)( 

CH2.CH2.NH.CH3 

This  compound  was  prepared  by  digesting  cotarnine  with  phenyl 
acetic  ester  in  alcoholic  solution  in  presence  of  sodium  carbonate, 
removing  the  unattacked  ester  by  means  of  ether  and  purifying  the 
condensation  product  by  precipitating  it  from  its  acid  solution  with 
sodium  carbonate  and  recrystallizing  from  alcohol.  The  anhydro- 
cotarnine  .phenyl  acetic  ester  forms  a  platinum  salt  and  a  diffi- 
cultly soluble  nitrate.  On  warming  it  with  hydrochloric  acid  the 
liquid  becomes  turbid  and  phenylacetic  ester  separates  out. 

Anhydrohydrastinine  phenylacetic  ester, 


\C02.C2H5 
C6H2(:02:CH2)( 

\ 
CH2.CH2.NH.CH3 


25 

was  prepared  by  the  same  method  as  the  preceeding  compound  but 
substituting  hydrastinine  for  cotarnine.  It  forms  a  platinum  salt 
but  no  difficultly  soluble  nitrate. 

Anhydrocotarnine  malonic  ester, 

CH  =  C(COa.C2H5)2 
C6H(:02:CH2)(O.CH3)( 

CH2.CH2NH.CH3. 

was  made  by  gently  warming  a  mixture  of  cotarnine  and  malonic 
ester  with  a  few  drops  of  piperidine  and  then  setting  the  mixture 
aside  for  twenty-four  hours.  The  malonic  ester  compound  is  very 
easily  decomposed  by  hot  solvents  or  by  digestion  with  hydrochloric 
acid.  On  trying  to  make  a  platinum  salt  of  it  by  adding  chloro- 
platinic  acid  and  the  calculated  amount  of  hydrochloric  acid,  the 
platinum  salt  of  cotarnine  itself  was  obtained  instead,  and  from  the 
mother  liquor  of  the  platinum  salt  it  was  possible  to  isolate  and 
identify  both  malonic  acid  and  malonic  ester,  showing  that  the  con- 
densation product  is  easily  transformed  into  cotarnine-malonate. 

Anhydromethyl  cotarnine  malonic  ester  iodomethylate, 

CH  =  C(CO2C2H5)2 
C6H(:0:CH2.)(6.CH3)( 

CH2.CH2.N(CH3)2CH3I 

was  formed  together  with  cotarnine  hydriodide  on  digesting  the  pre- 
ceeding malonic  ester  condensation  product  with  methyl  iodide  at 
ordinary  temperature  and  removing  the  hydriodide  by  washing  with 
cold  water  in  which  the  salt  is  much  more  soluble  than  the  qua- 
ternary compound.  The  iodomethylate  was  then  recrystallized  from 
hot  water. 

Anhydrohydrastinine  malonic  ester, 
\ 

CH=C(C02.C2H5)2 
C6H2(:02:CH2)( 

CH2  CH2.NH.CH3 

was  obtained  by  the  same  method  as  was  used  for  the  preparation 
of  the  corresponding  cotarnine  compound.  As  the  hydrastinine  com- 


26 

pound  is  very  easily  soluble  in  alcohol  it  was  isolated  by  concen- 
trating the  alcoholic  solution  in  vacuum  over  calcium  chloride,  then 
taking  up  the  residue  with  ether  and  evaporating  the  ether  in 
vacuum.  The  hydrastinine  compound  becomes  yellowish  on  exposure 
to  light  and  is  as  easily  decomposed  as  the  corresponding  cotarnine 
compound.  As  in  the  case  of  the  cotarnine  compound  the  anhydrohy- 
drastinine  compound  easily  breaks  up  and  no  chloroplatinate  could 
be  obtained :  the  compound  breaks  up  and  the  chloroplatinate  of 
hydrastinine  is  formed  instead  of  the  chloroplatinate  of  the  conden- 
sation product. 

Anhydrocotarnine  coumarone, 

(Ci2Hi4N03).(C8H50) 

was  made  by  digesting  cotarnine  with  coumarone  in  alcoholic  solu- 
tion in  presence  of  sodium  carbonate  and,  after  24  hours'  standing, 
precipitating  the  condensation  product  with  water.  It  was  purified 
by  dissolving  it  in  hydrochloric  acid,  precipitating  the  solution 
with  sodium  'carbonate,  then  redissolving  the  precipitate  in  ether 
and  precipitating  it  again  with  ligroin.  The  compound  forms  a 
yellow  flocculent  platinum  salt. 

Anhydrohydrastinine  coumarone. 

(CiiHi2N02).(C8H50) 

was  prepared  in  the  same  way  as  the  preceeding  compound.  It  forms 
a  platinum  salt  and  dissolves  in  concentrated  sulphuric  acid  with 
violet  color. 

Anhydrocotarnine  resorcin, 

(Ci2Hi4N03).[C6H3(OH)2] 

can  be  made  either  by  dissolving  each  of  the  components  in  alcohol, 
mixing  the  two  solutions  and  then  warming  the  mixture  to  60°  or 
by  dissolving  cotarnine  in  dilute  sulphuric  acid  and  adding  to  this 
solution  an  alcoholic  solution  of  resorcin.  After  standing  a  few  days 
the  liquid  is  diluted  with  water  and  the  condensation  product  pre- 
cipitated with  sodium  carbonate.  The  compound  is  easily  soluble  in 


27 

dilute  acids  and  is  reprecipitated  from  acid  solutions  by  potassium 
'hydrate  or  potassium  carbonate.  An  excess  of  potassium  hydrate 
redissolves  the  precipitate.  It  forms  a  hydrochloride  which  is  diffi- 
cultly soluble  in  hydrochloric  acid.  Boiling  hydrochloric  acid  decom- 
poses the  condensation  product  only  slowly  and  incompletely  into 
its  component  parts.  Ber.  Dtsch.  Chem.  Ges.,  1904,  p.  2738. 

L.  Kropf  has  made  some  condensation  products  of  cotarnine  and 
tried  to  establish  the  formulae  of  these  compounds  by  proving  the 
presence  or  absence  of  a  hydrogen  atom  attached  to  the  nitrogen 
atom  in  these  compounds.  (See  the  two  preceeding  paragraphs.) 
In  anhydrocotarnine  acetophenone  and  anhydrocotarnine  acetone 
the  presence  of  such  an  atom  was  shown  by  the  fact  that  these  com- 
pounds can  be  converted  into  acetyl  and  benzoyl  derivatives.  It 
was  found  that  the  benzoyl  derivative  made  from  anhydrocotarnine 
acetone  was  identical  with  the  compound  made  by  condensing  acetone 
with  benzoyl  cotarnine  in  which  the  benzoyl  group  has  the  same 
position  as  the  hydrogen  atom  in  cotarnine,  i.  e.,  it  must  be  attached 
to  the  nitrogen  atom.  These  condensation  products  must  correspond, 
therefore,  to  formula  (I).  (See  preceeding  paragraph). 

In  the  reaction  of  some  of  these  compounds  with  methyliodide 
they  also  seem  to  correspond  to  formula  (I).  When  anhydrocotar- 
nine acetophenone  is  treated  with  methyliodide  two  compounds  are 
obtained  according  to  whether  the  reaction  takes  place  in  the  cold 
or  with  the  aid  of  heat.  In  the  cold  the  iodomethylate  of  anhydro- 
methylcotarnine  acetophenone  is  formed  together  with  the  hydriodide 
of  anhydromethylcotarnine  acetophenone.  In  the  heat  the  hydrio- 
dide of  anhydromethylcotarnine  acetophenone  is  formed.  These  com- 
pounds too  must  correspond  to  formula  (I)  and  their  formation  can 
be  expressed  by  following  equations: 

1.  In  the  cold.    2Ci9Hi704NH.CH3  4-  2CH3I  =  Ci0Hi704N(CH8)8l 
+  CieHi704NH.CH3.HI. 

2.  In  the  heat.  Ci0Hi704NH.CH8  +  CHaI  =  Ci9Hi704N(CH3)2.HI. 

On  the  other  hand  the  compounds  obtained  by  condensing  cotar- 
nine with  ethylacetoacetic  ester  or  benzylacetoacetic  ester  both  of 
which  contain  only  one  hydrogen  atom  attached  to  the  carbon  atom 
which  takes  part  in  the  condensation,  must  correspond  to  formula 


28 

(II),  tliat  is,  the  alkaloid  must  be  supposed  to  react  in  the  tauto- 
meric  form  containing  a  OH  group  which  is  eliminated  with  the 
hydrogen  atom  of  the  esters  as  water. 


Experimental.  Anhydrocotarnine  acetylacetone  C 
was  prepared  by  warming  molecular  quantities  of  cotarnine  and 
acetylacetone  in  presence  of  alcohol  and  some  saturated  solution  of 
sodium  carbonate.  On  slowly  cooling  the  liquid  and  adding  water 
to  it  the  condensation  product  is  precipitated  as  a  yellowish  white 
crystalline  powder.  It  was  purified  by  solution  in  dilute  hydrochloric 
acid  and  recrystallization  from  diluted  alcohol.  It  forms  a  hydro- 
chloride  which  can  be  obtained  by  passing  hydrochloric  acid  gas  into 
its  ethereal  solution  and  recrystallizing  the  salt  from  ether-alcohol. 
The  hydrochloride  is  very  hygroscopic.  A  platinum  salt  was  prepared 
which  crystallizes  in  yellow  needles  and  is  quite  soluble  in  warm 
water. 

Anhydrocotarnine  acetonylacetone,  CisH^sNOs,  was  made  by 
warming  an  alcoholic  solution  of  the  components  in  presence  of  some 
sodium  carbonate,  then  adding  to  the  cooled  mixture  enough  hydro- 
chloric acid  to  make  a  clear  solution  and  precipitating  the  conden- 
sation product  with  sodium  carbonate.  The  oily  liquid  which  sepa- 
rates out  is  taken  up  with  ether,  the  ether  evaporated  and  the  re- 
sidue, after  solution  in  hydrochloric  acid,  again  precipitated  with 
sodium  carbonate.  The  precipitate  is  again  dissolved  in  ether  and 
the  ether  removed  by  evaporation.  The  condensation  product  forms 
a  white  crystalline  powder  which  is  very  easily  soluble  in  alcohol  or 
ether  but  insoluble  in  water.  It  forms  a  hygroscopic  hydrochloride 
and  a  yellow  flocculent  platinum  salt. 

Anhydrocotarnine  acetoacetic  ester,  Cigt^aNOe,  was  made  in  the 
same  way  as  the  acetylacetone  compound.  It  forms  a  hygroscopic 
hydrochloride  and  a  platinum  salt. 

Anhydrocotarnine  benzoylacetoacetic  ester,  C23H24NO**,  was  ob- 
tained in  the  same  way  as  the  preceeding  compound.  By  the  same 
method  was  prepared  anhydrocotarnine  cyanoacetoacetic  ester, 
CiyHao^Os.  The  cyanogen  compound  cannot  be  dissolved  in  hydro- 
chloric acid  without  decomposition  and  on  trying  to  make  a  platinum 
salt  of  it  the  platinum  salt  of  cotarnine  was  formed. 


29 
Anhydrocotarnine  ethylaceto  acetic  ester, 

/C2H5 

CH3.O  CH C— CO.CHs 

/\        /\  \ 

O/        \/        \N.CH3       \CO2.C2H5 

CH  /    I  I 

.    CH2x   !          ! 

0\        /\        /CH2 
\/         \/ 
CH2 

was  prepared  by  the  same  method  as  the  acetoacetic  ester  compound. 
It  could  riot  be  obtained  in  solid  condition  and  was,  therefore,  con- 
verted into  the  hydrochloride  for  analysis. 

The  corresponding  benzylacetoacetic  ester  compound  was  obtained 
by  the  same  method  in  the  form  of  an  oil.  It  gives  a  hydrochloride 
and  a  platinum  salt. 

lodomethylate  of  anhydromethylcotarnine  acetophenone,  C22H26 
04NI,  was  obtained  by  digesting  the  components  under  cooling  and 
removing  the  hydriodide  of  anhydrocotarnine  acetophenone  formed 
at  the  same  time  by  washing  with  a  little  water  or  alcohol  in  which 
the  hydriodide  is  more  soluble  than  the  iodomethylate.  The  iodo- 
methylate  forms  yellowish  white  needles  quite  soluble  in  warm  alcohol 
or  warm  water.  It  is  not  precipitated  from  its  aqueous  solution  by 
alkalies  or  alkaline  carbonates. 

If  methyliodide  and  cotarnine  acetophenone  are  made  to  react 
upon  each  other  without  cooling  the  mixture  becomes  hot  and  on 
cooling  the  hydriodide  of  anhydromethylcotarnine  acetophenone 
separates  out  in  crystals.  From  the  hydriodide  the  free  anhydro- 
methylcotarnine acetophenone  is  precipitated  by  alkalies  or  alkaline 
carbonates  as  an  oily  liquid  which  very  soon  becomes  crystalline. 
The  base  dissolves  in  concentrated  sulphuric  acid  with  a  red  color. 

Acetyianhydrocotarnine  acetophenone, 

Ci9Hi704[N.(CH3). (CO.CHs)] 

was  prepared  by  digesting  on  the  water  bath  anhydro-cotarnine 
acetophenone  with  acetic  anhydride.  The  liquid  was  then  boiled  with 
water  and  after  cooling  the  acetyl  derivative  precipitated  with  sodium 
carbonate.  The  acetyl  compound  is  oily  at  first  but  soon  becomes 


30 

crystalline.  It  dissolves  in  concentrated  sulphuric  acid  with  a  blood- 
red  <  olor. 

Benzoylanhydrocotarnine  acetophenone 

Ci9Hi704N(CH3).(CO.C6H5) 

was  made  by  benzoylating  anhydrocotarnine  acetophenone  by  Schot- 
ten-Baumann's  method.    The  benzoyl  compound  is  easily  soluble  in 
alcohol  but  insoluble  in  water  or  dilute  acids.    It  dissolves  in  con- 
centrated sulphuric  acid  with  red  color. 
Benzoylanhydrocotarnine  acetone, 

CiiHi504N(CH3).(CO.C6H5) 

was  made  by  benzoylating  anhydrocotarnine  acetone  by  Schotten- 
Baumann's  method.  It  is  oily  at  first  but  becomes  crystalline  in 
vacuum.  It  is  easily  soluble  in  alcohol  but  insoluble  in  water  or 
dilute  acids. 

The  compound  can  be  made  by  condensing  benzoylcotarnine 
(Ann.  d.  Chem.  254,  335)  with  acetone.  For  this  purpose  the  benzoyl- 
cotarnine is  warmed  with  acetone  on  the  water  bath  in  presence  of 
some  alcoholic  potassium  hydrate.  After  twelve  hours  the  benzoyl- 
ated  condensation  product  separates  out  in  crystals. 

Ber.  Dtsch.  Chem.  Ges.,  1904,  p.  2744. 

C.  Renz  and  M.  Hoffmann  have  tried  to  condense  tetrahydro- 
methoxyquinoline  (the  sulphate  of  which  is  used  under  the  name  of 
thalline)  and  cotarnine  with  aldehydes  and  phtalic  anhydride.  No 
condensation  product  could  be  obtained  from  thalline  and  aldehydes 
but  with  phtalic  anhydride  a  definite  compound  was  obtained  accord- 
ing to  following  equation : 

C]0Hi3NO  +  C6H4(CO)20  =  CisHisNOs  +  H20 
Whether  the  two  hydrogen  atoms  which  go  out  with  one  oxygen 
atom    of   the   anhydride   as    water   come   from    the    methyl   group 
situated  in  the  benzol  ring  or  from  the  reduced  pyridine  ring  has  not 
yet  been  established. 

1.  Thalline  with  phtalic  anhydride.  The  condensation  of  thalline 
with  phtalic  anhydride  was  effected  by  heating  molecular  quantities 
of  the  substances  to  370°  and  boiling  the  yellow  vitreons  reaction 
product  with  alcohol.  The  condensation  product  is  insoluble  in 
dilute  acids  or  alkalies,  soluble  in  boiling  glacial  acetic  acid  and 
strong  sulphuric  acid  and  slightly  soluble  in  concentrated  hydro- 


31 

chloric  acid  and  benzol.    It  has  the  formula  2 
Boiling  nitric  acid  does  not  nitrate  but  oxidizes  it. 

2.  Cotarnine  with  aldehydes.  On  boiling  molecular  quantities  of 
cotarnine  and  vanilin  in  alcohol  in  presence  of  some  potassium 
hydrate  and,  after  acidulating  with  hydrochloric  acid,  evaporating 
off  the  alcohol  a  compound  was  obtained  having  the  formula 
C2oHi7Np4  +  HCl  +  HaO.  The  compound  is  quite  soluble  in  water 
but  difficultly  soluble  in  hydrochloric  acid.  The  yellow  solution  of 
the  hydrochloride  is  colored  red  by  ammonia.  On  standing  the  red 
color  disappears.  The  free  base  could  not  be  isolated. 

On  substituting  in  the  above  reaction  protocatechuic  aldehyde 
for  vanilin  a  compound  was  obtained  having  the  formula  CigHioNOe. 
HC1  +  H20.  This  compound  too  is  colored  red  by  ammonia.  Neither 
the  free  base  nor  a  gold  or  platinum  salt  of  the  compound  could  be 
obtained.  Ber.  Dtsch.  Chem.  Ges.,  1904.  p.  1962. 

M.  Freund  finds  that  on  subjecting  cotarnine  or  its  hydrochlo- 
ride or  cyanide  to  Grignard's  reaction  a-substituted  derivatives  of 
hydrocotarnine  can  be  obtained.  For  example,  with  CHs.Mg.I  we 
get  a-methylhydrocotarnine 

CH3.0  COH  CH3.O  CH.CH3 

0/\/\N.CH3 


CH2( 


O 


_>    CH2( 


CH2 


CH2.CH2.NH.CH3  CH2 


In  the  same  way  can  be  prepared  compounds  containing  instead 
of  the  methyl  group  the  ethyl,  propyl,  isobutyl,  phenyl,  /2-naphtyl 
and  benzyl  groups. 

If  in  Grignard's  reaction  allyliodide  or  polyhalogen  derivatives 
of  the  hydrocarbons  be  used  there  is  always  formed  di-hydrocotarnine 


CH3.0  CH—  — HC  O.CH3 

/\       /\  /\       /\ 

O/        \/'        \N.CH3  CH3.N/       \/       \O 


CH2: 


ol 


CH2  H2C\ 

\x      \/  \/      \/ 

CH2  H2C 

Di-hydrocotarnine. 


CH: 


32 


According  to  an  observation  of  Roser  when  cotarnine  is  condensed 
with  benzylcyanide  anhydrocotarnine  benzylcyanide  is  formed  which 
is  decomposed  by  acids  into  its  components. 


CH.s.O  CH  — C.(CN).CeH5 

0/\/ 


CH2( 


0\       /\ 


CH2.CH2.NH.CH3 
Anhydrocotarninebenzylcyanide. 

This  compound  when  treated  with  methyliodide  is  converted  into 
the  iodomethylate  of  anhydrocotarnine  methine  benzylcyanide, 
(CH30).(CH202).C6H[CH:C.(CN).C6H5].CH2CH2.N(CH3)3l,  which  is 
decomposed  by  warm  alkalies  with  the  elimination  of  trimethyl- 
amine. 

The  author  intends  to  convert  the  anhydrocotarnine  benzyl- 
cyanide  into  the  corresponding  dibromide  from  which  it  ought  to  be 
possible  to  eliminate  hydrobromic  acid  with  the  closing  of  the  side 
chain  into  a  ring: 

CH3O  CH=C(CN)C6H5 

/\       / 
OX        \/ 

/  I          I  > 

\  | 

o  \      /\ 
\x     \ 

CH2.CH2NH.CH3 


CHs.O  CHBr.CBr(CN).C6H5 

/\        / 
O/         \/ 


CH< 


o\      /\ 

\X       CH2.CH2.NH.CH3 


CH3.0  CH-CBr(CN)C6H5 

/\        /\ 
^/  \N.CH3 

CH2( 

O  \        /\        /CH2 
\/        \X 

CH2 


38 

The  author  also  finds,  that  berberinal  which  in  some  respects 
resembles  cotarnine  and  hydrastinine  is  converted  by  means  of  alky] 
magnesium  iodide  into  '/-alkyldihydroberberine: 

O CH2 


/      \o 

1 

COH 

/\        /                  / 

1 

CH3 

.O/                         HN/ 

\                / 

\/ 

1             1                    1 

1 

|             j 

CHo 

CH3 

.()\        /\             ^C\ 

|  V>  l   I  _ 

\/        XCH^?^        \/ 

CH2 

Berberinal. 


O CH2 

R  '  \0 

CH 

/\   N  /\        / 
\/       \S       \/ 

/\        /\        /CH2 
%/  C  \^'  C  \/ 
CH         CH2 

^-Alkyldihydroberberine. 

Ber.  Dtsch.  Chem.  Ges.  1904,  3334. 

M.  Freund  und  H.  Beck  have  investigated  the  action  of  chronic 
acid  upon  N-methyltetrahydroisoquinoline. 

As  Beckett  and  Wright  had  previously  shown  (Journ.  Chem  Soc. 
1876,  577)  hydrocotarnine  is  oxidized  by  chromic  acid  to  a  salt  of 
cotarnine : 

CHg.O   CH2 
/\        /\ 
O/        \/         \N.CH3 


CH 


H2S04 


O\        /\ 

\/        \/ 
CH2 

Hydrocotarnine. 


34 

CH3.0  CH          CH3 
/\        /  \       / 
O/        \/       \N 
CH2/|  I 

HS04  +  H20 
O\        /\        /CH2 

\/       \/ 

CH2 

Cotarnine  acid  sulphate. 

Later  it  was  shown  by  Freund  and  Will  (Ber.  Dtsch.  Chem.  Ges. 
1887,  2403)  that  hydrohydrastinine  which  is  very  nearly  related  to 
hydrocotarnine  behaves  in  the  same  way  with  chromic  acid. 


CH2 

X\        /\ 
O/        \X        \N.CH3 


CH2( 


O\ 


\ 


H2S04  +  O  = 


vx 


CH2 
Hydrohydrastinine. 


CH 


/\ 


CH2 


O/ 
/| 

\   | 
O\ 


CH3 


HS04 


+H2O 


CH2 
Hydrastinine  acid  sulphate. 

On  adding  alkali  to  these  salts  of  cotarnine  and  hydrastinine 
the  bases  are  set  free.  In  this  reaction  the  reduced  pyridine  ring  is 
opened  up  with  the  formation  of  an  aldehyde  group  and  a  methyl- 
imide  group: 


CH3.O 

o/ 

/| 
! 

O\ 


CH 


N 


/\        /CH2 
/        \/ 
CH2 

Cotarnine  acid  sulphate. 


35 

CHs.O  COH 

O/       \/ 

'   I  I 

o\     /\ 

\X       CH2  CH2.NH.CH3 
Cotarnine. 


As  N-methyltetrahydroisoquinoline  is  the  parent  substance  of 
these  ba,ses  it  .was  natural  to  suppose  that  when  subjected  to  the 
action  of  chromic  acid  it  would  give  substances  similar  to  the  salts 
of  cotarnine  and  hydrastinine  and  that  when  these  substances  are 
treated  with  alkali  they  would  be  converted  into  compounds  contain- 
ing a  COH  and  an  NCHs  group. 


CH2  CH         CH3 

/\       /\  /\       /\      / 

>        XX       XN.CHs  /       \/      \N 

I  I  I  >      I  I  !     X 

|       ,  |        HS04 

\        /\        /CH2  \        /\        / 

\/        \/  \/         \/ 

CH2  CH2 

N-Methyltetrahydroisoquinoline. 


COH 


\        /\ 
\/        \ 

CH2.CH2.NH.CH3 


Experiments  have  not  corroborated  these  suppositions.  Whereas 
hydrocotarnine  and  hydrohydrastinine  are  easily  attacked  by  chromie 
acid  N-methyltetrahydroisoquinoline  reacts  very  slowly  with  this 
oxidizing  agent  and  the  substance  obtained  by  the  oxidation  seems 
to  have  an  entirely  different  constitution.  It  has  the  formula 
CioH7N03  and  its  constitution  seems  to  be  that  of  a  1,  3,  4,  -trike- 
to-N-methyltetrahydroisoquinoline. 


36 

(I) 

CO 
X\       /\ 

\/    i   \N.CH3 

I  2i 

A  4  /co 
\x     \/ 

CO 


This  compound  reacts  with  hydroxylamine  forming  an  oxime, 


N.CH3 


is  oxidized  by  potassium  permanganate  to  the  methylimide  of  phtalic 
acid 

(HI) 


-CO, 
-GO' 


N.CH3 


and  when  boiled  with  alkalies  evolves  methylamine  with  the  formation 
of  an  acid  which  was  not  investigated. 

The  N-methyltetrahydroisoquinoline  for  this  work  was  obtained 
by  the  method  of  Wedekind  and  Oechsler  (Ber.  Dtsch.  Ges.,  1902, 
3987)  and  its  oxidation  effected  by  means  of  potassium  dichromate 
in  presence  of  a  large  excess  of  sulphuric, acid  choosing  the  amount 
of  the  dichromate  so  as  to  have  six  atoms  of  oxygen  for  one  mole- 
cule of  the  base.  The  triketocompound  (1)  was  recrystallized  from 
hot  alcohol.  It  is  not  effected  by  dilute  acids  and  is  soluble  in  cold 
alkalies  and  hot  solutions  of  sodium  carbonate  or  ammonia.  From 
these  alkaline  solutions  the  triketocompound  cannot  be  recovered 
unchanged  by  addition  of  acid. 

The  monoxime   (II)  was  obtained  by  digesting  the   triketoeom- 


37 

pound  with  a  solution  of  hydroxylamine  hydrochloride  and  concen- 
trating- the  solution  to  a  small  bulk. 

The  oxidation  of  the  triketocompound  was  carried  out  by  dis- 
solving it  in  an  excess  of  potassium  hydrate,  adding  a  three  per 
cent  solution  of  potassium  permanganate  and  boiling  the  liquid  for 
some  time.  On  shaking  out  the  mixture  with  ether  and  recrystalliz- 
ing  the  substance  from  alcohol  after  evaporation  of  the  ether,  the 
compound  was  identified  by  comparing  it  with  the  methylimide  of 
phtalic  acid  (III)  which  was  prepared  by  neutralizing  phtalic  acid 
with  methylamine,  evaporating  the  liquid  to  dryness  and  melting  the 
residue. 

On  boiling  the  triketocompound  with  a  50%  solution  of  potassium 
hydrate  till  the  evolution  of  methylamine  ceased  and  shaking  out, 
the  liquid  with  ether  after  a  cidulating  with  sulphuric  acid  a  cry- 
stalline acid  substance  was  obtained  which  gave  crystalline  barium 
and  silver  salts.  It  was  free  from  nitrogen  and  seemed  to  have  the 
formula  Ci5Hi207.  Ber.  Dtsch.  Chem.  Ges.,  1904,  p.  1942. 

Cytisine.  According  to  M.  Freund  when  cytisine  is  heated  to 
225°— 230°  for  four  hours  with  strong  hydriodic  acid  and  red  phos- 
phorus the  alkaloid  breaks  up  into  cytisoline,  /2-cytisolidine  and  a 
complicated  mixture  of  hydrocarbons. 

Cytisoline,  CnHnNO.  The  formation  of  cytisoline  from  cytisine 
takes  place  according  to  following  equation : 

CnHi4N20  ==  CuHnNO  +  NH3 

Cytisoline  crystallizes  from  alcohol  in  needles  melting  at  199°. 
Chromic  acid  in  aeetic  acid  or  dilute  sulphuric  acid  solution  oxidizes 
cytisoline  to  cytisolinic  acid  which  would  seem  to  indicate  the  pres- 
ence of  a  CHs  group  in  cytisoline: 

CioH8(CH3)NO  — >  Ci0H8(C02H)NO. 

The  cytisolinic  acid  was  purified  by  solution  in  hot  glacial  acetic 
acid  and  precipitation  with  water.  The  acid  crystallizes  in  small 
needles  melting  above  350°.  It  is  soluble  in  ammonia  and  is  repri- 
citated  from  the  ammoniacal  solution  by  mineral  acids.  It  is  a  very 
stable  substance  not  being  affected  by  strong  nitric  acid  or  strong 
potassium  hydroxide.  A  mixture  of  nitric  and  sulphuric  acids  con- 
verts cytisoline  into  nitrocytisoline  which  forms  yellow  crystals  be- 
ginning to  sinter  at  240°  and  melting  at  275°. 


38 

Sodium  in  absolute  alcohol  reduces  cytisoline  to  a-cytisolidine, 
N,  which  is  isomeric  with  /8-cytisolidine  obtained  by  the  action 
of  hydriodic  acid  and  phosphorus  upon  cytisine.  The  «-cytisolidine 
is  an  oily  liquid  of  a  strong'  odor  and  forms  a  crystalline  chloro- 
platinate  and  an  oily  picrate  (difference  from  /J-cytisolidine  which 
forms  a.  crystalline  picrate). 

/2-Cytisolidine,  CnHi5N.  As  said  above  this  compound  is  formed 
together  with  cytisoline  by  the  action  of  strong  hydriodic  acid  upon 
cytisine  in  presence  of  amorphous  phosphorus.  The  two  bases  were 
separated  from  each  other  by  ether  which  removes  the  weakly  basic 
cytisoline  leaving  the  strongly  basic  /?-cytisolidine  in  the  aqueous  solu- 
tion. The  /3-cytisolidine  was  then  distilled  with  steam  into  dilute  hydro- 
chloric acid  and  converted  first  into  a  chloroplatinate  and  then  (after 
removing  the  platinum  by  t^S)  into  a  picrate.  The  chloroplatinate 
melted  at  207°.  The  picrate  is  at  first  semisolid  but  when  rubbed 
with  a -glass  rod  becomes  crystalline.  It  melts  at  228°. 

On  decomposing  the  picrate  of  /3-cytisolidine  with  sodium  hydrox- 
ide, distilling  off  the  /3-cytisolidine  and  converting  it  again  into  a 
chloroplatinate  the  latter  was  found  to  have  a  melting  point  of 
235°.  Hence  the  above  mentioned  chloroplatinate  of  /?-cytisolidine 
of  the  melting  point  207°  which  was  obtained  directly  without  pass- 
ing through  the  picrate  must  have  been  impure. 

Ber.  Dtsch.  Chem.  G.  1904,  16. 

Damascenine,  CgHnNOs.  H.  Pomrnerehne  shows  that  when 
damascenine  is  heated  with  hydriodic  acid  one  methyl  group  is 
eliminated  and  the  demethylized  alkaloid  is  left  in  the  form  of  a 
hydriodide  crystallizing  in  colorless  plates  and  melting  at  198°— 200°. 
The  hydriodide  was  converted  into  the  corresponding  hydrochloride 
by  means  of  silver  chloride.  The  hydrochloride  crystallizes  in  color- 
less spherical  forms  melting  at  217° — 218°. 

Owing  to  the  strong  reducing  properties  of  the  demethylized 
damascenine  no  gold  or  platinum  salt  could  be  obtained  from  it. 
An  attempt  to  acetylize  it  was  likewise  unsuccessful. 

On  heating  damascenine  hydrochloride  with  barium  hydrate  the 
alkaloid  undergoes  the  same  internal  rearrangement  as  when  boiled 
with  alcoholic  potassium  hydrate,  i.  e.;  the  base  is  changed  into  an 
acid-like  substance  which  has  the  same  formula  as  damascenine  but 
is  capable  of  combining  with  bases.  (See  Arch.  d.  Pharm.  1901,  35.) 


39 

The   barium    compound    of   this    new    substance    has    the    formula 
(CgHioNOa^Ba-fCoHnNOs.    The  solution  of  the  barium  salt  is  pre- 
cipitated by  silver  nitrate  and  lead  acetate  but  not  by  copper  acetate 
The  barium  salt  does  not  reduce  Fehling's  solution. 

On  acidulating  the  solution  of  the  barium  salt  with  acetic  acid 
the  same  fluorescent  substance  was  obtained  which  was  described  in 
aprevious  paper  (loc.  cit.). 

Barium  permanganate  oxidizes  damascenine  hydrochloride  to 
oxalic  acid  with  the  formation  of  methylamine  and  ammonia.  By 
chromic  and  sulphuric  acids  damascenine  is  decomposed  into  ammo- 
nia and  some  other  products  which  could  not  be  isolated  in  definite 
forms.  The  same  was  true  when  the  alkaloid  was  heated  with  soda- 
lime  or  zinc  dust.  Arch.  d.  Pharm.  1904,  295. 

0.  Keller  has  investigated  the  action  of  bromine,  acetyl  chloride 
and  acetic  anhydride  upon  damascenine  and  the  nature  of  the  com- 
pound which  is  formed  by  internal  rearrangement  of  the  alkaloid 
when  treated  with  alkalies.  (See  preceeding  paragraph.)  For  the 
acid-like  substance  into  which  damascenine  is  converted  by  alkalies 
the  name  damascenine  S  is  proposed. 

The  hydrochloride  of  damascenine  was  found  to  contain  one 
molecule  of  water  of  crystallization.  Upon  heating  to  90° — 100°  the 
hydrochloride  loses  both  acid  and  base. 

On  adding  bromine  dissolved  in  absolute  alcohol  to  a  solution  of 
damascenine  in  absolute  alcohol  a  hydrobromide  of  dibrom damas- 
cenine, CgHiiB^NOs.HBr,  was  obtained.  The  hydrobromide  is  easily 
soluble  in  water,  difficultly  soluble  in  absolute  alcohol  and  almost 
insoluble  in  ether.  Melting  point  198°— 201°.  Silver  nitrate  in 
aqueous  solution  .  precipitates  all  the  bromine  of  the  hydrobromic 
acid  of  the  compound  together  with  a  small  amount  of  the  additive 
bromine. 

Acethyl  chloride  or,  better,  acetic  anhydride  converts  damas- 
cenine into  a  monoacetyl  derivative,  CoHioCCHs.CX^NOs.  The  acetyl 
compound  crystallizes  in  plates  or,  needles  melting  at  203°— 204°,  is 
easily  soluble  in  alcohol  and  difficultly  soluble  in  water  or  ether. 

The  conversion  of  damascenine  into  damascenine  S  is  best  effected 
by  adding  potassium  hydrate  to  a  solution  of  damascenine  hydro- 
chloride  in  five  times  its  amount  of  alcohol  till  the  reaction  is  alka- 
line and  then  adding  enough  water  to  redissolve  the  potassium 
chloride  which  has  separated  out.  The  damascenine  S  crystallizes  in 


40 

plates  or  prisms  containing  three  molecules  of  water  of  crystalliza- 
tion and  melting  at  78°.  Anhydrous  the  substance  melts  at  143°— 
144°.  It  is  easily  soluble  in  water  or  alcohol  but  difficultly  soluble 
in  ether,  chloroform  or  ethyl  acetate.  The  aqueous  solution  of 
damascenine  S  has  an  acid  reaction  and  decomposes  carbonates. 
The  solutions  in  ether,  alcohol  or  chloroform  have  a  pretty  blue 
fluorescence.  The  acid  can  be  obtained  directly  anhydrous  by  re- 
crystallizing  it  from  a  mixture  of  alcohol  and  chloroform.  As  a  base 
it  forms  a  hydrochloride,  a  sulphate  and  a  platinum  salt.  It  also 
forms  a  silver  salt,  CoHioAgN03+ HaO,  which  is  soluble  in  nitric 
acid  and  ammonia  but  insoluble  in  cold  water.  Hot  water  decom- 
poses the  silver  salt. 

A  hydrochloride  of  the  methyl  ester  of  damascenine  S, 
C9Hio(CH3)N03.HCl  + H2<3,  was  obtained  in  hygroscopic  needles, 
melting  at  199°— 200°. 

By  the  action  of  bromine  upon  damascenine  S  a  dibrom-addition 
compound  was  obtained  which  was  different  from  dibromdamascenine 
showing  that  bromine  does  not  cause  the  internal  rearrangement  of 
the  alkaloid.  On  the  other  hand  on  converting  damascenine  S  into 
a  monoacetyl  derivative  by  means  of  acetic  anhydride  the  product 
was  found  to  be  identical  with  the  acetyl  compound  obtained  from 
damascenine  under  the  same  conditions.  Hence  in  the  acetylization 
the  alkaloid  is  transformed  into  the  acid-like  substance. 

By  the  action  of  methyliodide  both  damascenine  and  damascenine 
S  are  converted  into  one  and  the  same  hydriodide  of  methyl  damas- 
cenine, CoHio(CH3)N03.HI +  H20,  showing  that  in  this  reaction  too 
the  alkaloid  is  changed  to  the  acid.  The  free  methyldamascenine 
was  obtained  from  the  hydriodide  by  means  of  sodium  carbonate. 
From  the  methyldamascenine  the  iodomethylate,C9Hio(CH3)N03.CH3l, 
was  prepared  by  means  of  methyliodide  in  methylalcoholic  solution. 

A  nitroso  derivative  of  damascenine  was  prepared  by  the  action 
of  nitrous  acid  upon  damascenine  or  damascenine  S. 

From  various  experiments  the  author  draws  the  conclusion  that 
there  are  in  damascenine  the  groups  O.CHs,  NH.CHs  and  C02H,  so 
that  the  formula  of  the  alkaloid  can  be  resolved  into  CeHsCO.CHs). 
NH.CH3.C02H. 

It  would  seem  that  damascenine  is  an  N-methyl  derivative  of 
orthoanisidine  carboxylic  acid.  Arch.  d.  Pharm.  1904,  299. 


41 

Bcgonine.  J.  Gadamer  and  T.  Amenomiya  continue  their  in- 
vestigations olf  the  optical  functions  of  the  assy  metric  carbon  atoms 
of  ecgonine.  It  was  shown  in  a  previous  paper  (Arch.  d.  Pharm. 
231),  603)  that  of  the  four  assymetric  carbon,  atoms  of  ecgonine  (I) 
1  is  levorotatory  and  2  dextrorotatory. 

23                                   23                               '2 
CH2 — CH CH.C02H         CH2 — CH CH.C02H         CH2 — CH C.CO2H 


i          14  !          ! 

N.CHs  CH.OH  N.CHa  CH 


I  il 

N.CH    CH 

I 


I        I  I        II 

[2 — CH CH2  CH2 CH CH  CH2 — CH CH2 

111 

(D  (ID  (HI) 

In  the  present  paper  it  is  shown  that  in  1-ecgonine  3  and  4  must 
he  levorotatory  whereas  in  d-'/'- ecgonine  3  is  levorotatory  and  4  dex- 
trorotatory. 

It  was  also  found  that  anhydroecgonine  must  correspond  to  for- 
mula (II)  containing  three  assymetric  carbon  atoms,  not  formula 
(III)  with  but  two  assymetric  carbon  atoms. 

This  formula  for  anhydroecgonine  must  be  adopted  on  ficcount 
of  following  considerations: 

1.  Einhorn  and  Tahara  (Ber.  Dtsch.  Chem.  Ges.  1893,  324)  ob- 
tained 'from  anhydroecgonine  an  acid  which  was  shown  by  Willstat- 
ter  to  have  the  constitution  of  a  cycloheptatrii'n  carboxylic  acid.  The 
formula  of  this  acid  must  be  either  (IV)  or  (V)  according  to  whether 
the  formula  of  anhydroecgonine  is  (II)  or  (III).  On  treating  this 
acid  with  alcoholic  potassium  hydrate  it  is  transformed  into  two 
new  compounds  which  are  both  isomeric  with  the  acid  and  must 
differ  from  each  other  only  in  the  position  of  the  double  binding 

CH=CH CH.CO.OH  CH==CH C.CO.OH 

I  II 
CH                                                                       CH 

II  I 
CH=CH CH                                             CH  =-  CH CH2 

(IV)  (V) 

As  in  all  such  transformations  the  double  bindings  generally 
move  towards  the  carboxyl  group  it  is  only  (IV)  which  can  give  two 
isomers  having  the  donble  bindings  nearer  to  the  carboxyl  group. 
Hence  the  acid  must  correspond  to  (II). 


42 

2.  The  high  specific  rotation  of  anhydroecgonine  can  be  explained 
only  by  assigning  to  it  formula  (II)  with  three  assy  metric  carbon 
atoms,  not  by  (III)  with  only  two  assymetric  carbon  atoms  of 
which  one  (I)  is  levo  and  the  other  (2)  is  dextro.  (See  Arch.  d. 
Pharm.  1901,  663.)  The  high  specific  rotation  is  also  accounted  for 
by  the  influence  of  the  inactive  CO. OH  group  and  of  the  double  bind- 
ings upon  the  increa.se  of  the  rotation.  This  influence  is  far  greater 
in  (II)  than  in  (III). 

The  assymetric  carbon  atom  (3)  must  have  a  levo  function  be- 
cause anhydroecgonine  hydrochloride  has  the  rotation  of  — 61.5° 
and  as  (1)  and  (2)  must  nearly  neutralize  each  other,  having  oppo- 
site rotations,  the  high  negative  rotation  of  anhydroecgonine  can 
only  be  explained  by  assuming  (3)  to  be  levo  and  by  the  proximity 
of  the  "strengthening"  group  CO.'OH  to  this  (3)  atom. 

This  assumption  of  the  levo  function  of  (3)  is  supported  by  the 
fact  that,  contrary  to  previous  statements  hydroecgonidine  (VI)  as 
found  by  the  authors  in  slightly  levorotatory.  As  in  hydroecgonidine 
the  "strengthening"  CO. OH  group  is  nearer  the  dextro  atom  (2) 
than  the  levo  atom  (I)  hydroecgonidine  ought  to  be  dextrorotatory 
but  as  it  is  levorotatory  this  must  be  due  to  the  levo  function  of 

(3)- 

CH2 CH- 

N.CH3 

CH2 CH CH2 

1 

Hydroecgonidine. 
(TI) 

The  function  of  the  (3)  atom  in  ecgonine  must  be  the  same  as 
in  anhydroecgonine  because  the  latter  is  formed  both  from  1-ecgonine 
and  d- ^"-ecgonine.  As  the  rotation  of  anhydroecgonine  is  not  changed 
by  heating  it  with  strong  alkalies  or  sodium  ethylate  whereas 
1-ecgonine  by  the  same  treatment  is  converted  into  d- ^-ecgonine  the 
conversion  of  1-ecgonine  into  d- ^-ecgonine  must  be  due  to  a  change 
in  the  function  of  the  atom  (4)  not  (3).  Hence  (3)  must  have  a 
levo  function  in  all  ecgonine  derivatives. 

As  to  the  function  of  the  atom  (4)  it  is  elear  that  in  1-ecgonine 
it  must  have  a  levo  function  as  otherwise  there  is  no  explanation 
for  the  formation  of  d- '/-ecgonine  from  it;  but  in  d- ^ecgonine  (d-ecgo- 


43 

nine)  the  atom  (4)  has  most  probably  a  dextro  function  and  the 
rotation  of  this  atom  to  the  right  in  d-ecgonine  is  equal  to  the  ro- 
tation of  (4)  to  the  left  in  1-ecgonine.  Arch.  d.  Pharm.  1904,  1. 

Bphedrine.  F.  Flaecher  finds  that  the  substance  formed  by 
heating  ephedrine  with  hydrochloric  acid  to  170°  and  named  by 
Nagai  (Cbem.  Ztg.  1890,  441)  isoephedrine  is  identical  with  pseudo- 
ephedrine  which  together  with  ephedrine  exists  in  Ephedra  vulgaris. 
The  identity  was  shown  by  comparing  the  crystalline  forms  and  the 
optical  rotations  of  both  the  free  bases  and  their  hydrochlorides. 
The  gold  salts  obtained  from  pseudoephedrine  and  isoephedrine  were 
also  found  to  be  identical.  Arch.  d.  Pharm.  1904,  380. 

E.  Fourneau  has  prepared  several  compounds  that  are  isomeric 
with  ephedrine,  CioHisNO.  Of  these  isomers  one  is  in  so  many 
respects  similar  to  the  natural  base  that  it  is  reasonable  to  assume 
that  the  synthetic  compound  is  the  optically  inactive  modification 
of  the  alkaloid.  This  isomer  of  ephedrine  was  prepared  by  the  action 
of  methylamine  upon  the  monochlorhydrine  of  phenyl-methylglycol : 

CH3  CH3 

HO.C C6H5  +  CH3NH2  =  HO.C C6H5  +  HC1 

CH2.C1  CH2.NH.CH3 

Monochlorhydrine  of  phenyl-       Methylamino-dimethyl-phenyl- 
methyl  glycol.  carbinol. 

The  artificial  base  is  a  colorless  liquid  boiling  at  145°  under  24 
mm.  pressure,  quite  soluble  in  cold  water,  but  insoluble  in  hot  water. 
It  slowly  reduces  potassium  permanganate  in  acid  solution  and  gives 
a  silver  mirror  with  silver  oxide.  The  salts  of  the  synthetic  base 
could  not  be  obtained  in  crystalline  form. 

Journ.  Pharm,  Chem.  1904,  XX,  481. 

Euquinine/CO(O.C2H5)(O.C2oH230N2).  P.  Cesaris  finds  that 
on  mixing  3.96  grams  of  euquinine  with  1.38  grams  of  salicylic  acid 
dissolved  in  100  c.  c.  of  absolute  alcohol  a  crystalline  compound 
soon  separates  out  which  is  colored  green  by  hydrochloric  acid,  sul- 
phuric acid  and  nitric  acid  and  melts  at  195°— 196°.  The  compound 
is  almost  insoluble  in  cold  water,  a  little  more  soluble  in  hot  water, 
easily  soluble  in  chloroform  and  hot  alcohol  and  difficultly  soluble 


44 

in  ether,  benzol  or  carbon  disulphide.  It  is  colored  red  by  ferric 
chloride  (reaction  of  salicylic  acid)  and  olive  green  by  chlorine  water 
and  ammonia  (euquinine  reaction).  Boll.  Chim.  Farm.  1904,  11. 

Hydrastinine.  C.  Liebermann  and  F.  Kropf  have  prepared 
anhydrohydrastinine  acetone  by  condensing  hydrastinine  with  acetone. 
The  reaction  is  the  same  as  with  cotarnine  (see  this  Review  page  160). 

The  anhydrohydrastinine  acetone  melts4  at  a  lower  temperature 
(72°)  than  hydrastinine  itself  (116° — 117°),  and  forms  a  hydro- 
chloride  and  a  platinum  salt  which  were  obtained  by  the  game 
methods  as  the  corresponding  cotarnine  compounds. 

In  the  same  way  was  obtained  a  condensation  product  of  hydra- 
stinine with  acetophenone.  The  anhydrohydrastinine  acetophenone 
is  easily  soluble  in  alcohol  with  fluorescence  and  crystallizes  in  prisms 
melting  at  74°.  It  also  forms  a  platinum  salt. 

Ber.  Dtsch.  Chem.  Ges.  1904,  214. 

J.  J.  Dobbie  and  C.  K.  Tinkler  investigating  the  absorption 
spectra  of  hydrastinine  and  its  salts  in  different  solvents  draw  the 
following  conclusions  in  regard  to  the  constitution  of  this  base: 

1.  In  the  solid  state 'or  in  solution  in  dry  ether  or  chloroform 
hydrastinine  is  colorless  and  must  be  assumed  to  have  the  carbinol 
form. 

CH.(OH).N.CH3 

CH2 CH2 

2.  In  the   colored  aqueous  or  alcoholic  solutions  the   alkaloid 
and  its  salts  have  the  ammonium  hydroxide  form 

OH 

C7H402/  CH* 

CH2-CH2 

« 

3.  Dissolved  in  little  alcohol  the  alkaloid  exists  in  both  forms, 
but  the  addition  of  much  alcohol  changes  the  colorless  carbinol  form 
completely  to  the  colored  ammonium  form.. 

4.  Alkalies  added  to  the  colored  solutions  of  hydrastinine  salts 
cause  a  reverse  change  from  the  ammonium  form  to  the  carbinol 
form. 


45 

The  complete  conversion  of  the  amonium  form  into  the  carbinol 
form  in  solution  by  the  addition  of  alkali  can  be  noticed  by  the  fact 
that  the  fluorescence  of  the  solutions  disappears  completely  when 
the  transformation  is  complete. 

The  author  draws  the  conclusion  that  the  open  chain  aldehyde 
formula  proposed  by  Roser  for  hydrastinine,  not  explaining  these 
differences  in  the  spectra,  cannot  be  correct. 

COH 


CH2.CH2.NH.CH3 
Iloser's  formula. 

Journ.  Chem.  Soc.  1904,  1005. 

Isopilocarpine.  H.  A.  D.  Jowett  finds  that  upon  melting  iso- 
pilocarpine,  CnHi6N202,  with  patassium  hydrate  normal  butyric 
acid  is  formed,  not,  as  previously  reported,  isobutyric  acid. 

Proc.  Chem.  Soc.  1904,  14. 

IvUpinidine.  K.  Willstiitter  and  W.  Marx  have  investigated 
the  composition  and  properties  of  lupinidine.  The  conclusions  arrived 
at  are  as  follows: 

1.  Lupinidine  is  identical  with  sparteine  both  alkaloids  having 
th«  same  formula,  CisEbe^,  and  agreeing  also  with  regard  to  boil- 
ing point,   specific  gravity,  solubilities  etc. 

2.  The  boiling  point  under  18  m.  m.  pressure  is  180.5°  and  under 
13  m.  m.  pressure  170.5°.    The  specific  rotation  in  pure  condition  is 
[a]20°—  —5.96°.    Dissolved  in  99%  alcohol  (C  =  14.206)  the  specific 
rotation  is  [«]2°°=  —16.41°. 

3.  Judging  from  the  empirical  formula  and  the  behavior  towards 
potassium  permanganate  there  cannot  be   any  double   bindings   in 
sparteine  and  the  molecule  must  be  made  up  of  one  aromatic  ring 
or  four  saturated  rings. 

4.  There  are  only  three  alkaloids  present  in  the  various  lupinus 
plants  :    lupinine,    CioHioNa,    in  Lupinus  luteus  and  Lnpinus  niger, 
sparteine,    CisHge^    in    Lupinus    luteus    and    Lupinus    niger,    and 
lupanine  CisH^^O    in  Lupinus    albus,    Lupinus    angustifolius    and 
Lupinus  perennis. 


46 

5.  Sparteine  is  very  difficultly  volatilized  with  steam,  has  a  very 
feeble  odor,  is  easily  soluble  in  benzol  or  ligroin  and  does  not  form 
a  hydrate.  On  titrating  sparteine  with  acids  the  amount  of  acid 
consumed  varies  with  the  concentration  of  the  alkaloidal  solution. 

The  statements  of  other  investigators  with  regard  to  these  points 
were  found  to  be  incorrect. 

Ber.  Dtsch.  Chem.  Ges.  1904,  2351. 

Lupinus  Alkaloids.  According  to  E.  Schmidt  the  alkaloids 
of  Lupinus  perennis  consist  chiefly  of  d-lupanine,  CisH24N20,  mixed 
sometimes  with  oxylupanine,  CisH24N202,  and  sometimes  with  other 
alkaloids.  Seeds  obtained  from  the  same  source  and  apparently 
having  the  same  morphological  characteristics  have  yielded  at  different 
times  different  alkaloids. 

On  the  suggestion  of  E.  Schmidt  some  analyses  and  molecular 
weight  estimations  of  lupinine  were  carried  out  by  G.  Fr.  Bergh.  The 
results  obtained  corroborated  the  statements  of  Willstatter  and 
Fourneau  with  regard  to  this  alkaloid  (Arch.  d.  Pharm.  240,  335.) 

Arch.  d.  Pharm.  1904,  409. 

G.  Fr.  Bergh  has  investigated  the  alkaloids  of  Lupinus  perennis. 
The  alkaloids  were  obtained  by  the  following  method.  The  coarsely 
powdered  seeds  were  extracted  with  water  acidulated  with  hydro- 
chloric acid,  the  liquid  concentrated  and  the  extract  after  making 
it  alkaline  with  sodium  hydroxide  extracted  first  with  ether  and  then 
with  chloroform.  In  this  way  an  ethereal  and  a  chloroform  extract 
were  obtained  wrhich  were  worked  up  separately. 

On  distilling  off  the  ether  from  the  ethereal  extract  and  treating 
the  residue  with  a  large  amount  of  ether  crystals  of  oxylupanine 
separated  out  on  the  walls  of  the  vessel  and  a  yellowish  red  sticky 
mass  settled  at  the  bottom.  This  mass  could  not  be  made  to 
crystallize.  From  the  ethereal  mother  liquor  some  d-lupanine  was 
obtained. 

The  chloroform  extract  after  distilling  off  the  solvent  was  mixed 
with  magnesium  oxide,  the  mass  thoroughly  dried  and  then  extracted 
for  a  month  with  ether  in  a  Soxhlet  apparatus.  On  distilling  off  the 
ether  the  residue  was  treated  again  with  a  large  amount  of  cold 
ether  which  removed  some  d-lupanine  and  the  remaining  oxylupanine 
recrystallized  from  a  mixture  of  acetone  and  water.  From  fifteen  kg. 


47 

of  the  seeds  15  grams  oxylupanine  and  200  grams  d-lupanine  were 
obtained. 

Oxylupanine,  CisH24N2O2+  2H20,  forms  colorless  transparent 
rhombic  prisms  and  melts  air  dried  at  76° — 77°;  dried  at  50° — 60° 
in  vacuum  it  melts  at  172° — 174°.  When  dried  under  ordinary 
pressure  at  100°  the  alkaloid  becomes  brown.  The  specific  rotation 
is  -f-  64.12.  The  alkaloid  forms  a  di-  and  a  mono-hydrochloride. 
When  the  dihydrochloride  is  melted  it  is  changed  to  the  monohydro- 
chloride.  Oxylupanine  also  forms  a  hydriodide,  a  chloraurate  and  a 
chloroplatinate.  The  salts  of  oxylupanine  crystallize  less  readily 
than  those  of  d-lupanine. 

The  two  alkaloids  can  be  distinguished  from  each  other  by  their 
behaviour  with  bromine  water;  with  which  d-lupanine  gives  a  fine 
precipitate  which  on  stirring  disappears,  whereas  oxylupanine  gives 
a  flocculent  amorphous  precipitate  which  does  not  disappear  on 
stirring. 

Monoacetyl  oxylupanine  CisH^a^C^CHsCO)  was  prepared  by 
boiling  oxylupanine  with  acetic  anhydride.  For  analysis  it  was  con- 
verted into  its  crystalline  chloraurate. 

Oxylupanine  iodomethylate,  CisH^C^^.CHsI-f  H^O,  was  pre- 
pared by  heating  the  alkaloid  A\ith  excess  of  methyliode  in  methyl- 
alcoholic  solution.  After  converting  the  iodomethylate  into  the 
chlorornethylate  the  latter  was  converted  into  the  gold  and  platinum 
salts. 

On  heating  oxplupanine  with  red  phosphorus  and  hydriodic  acid 
it  is  converted  into  lupanine. 

d-Lupanine  forms  a  hydriodide  which  crystallizes  with  two  mole- 
cules of  water  of  crystallization.  The  salt  cannot  be  dried  under 
ordinary  pressure  without  decomposition  and  loses  its  water  of 
crystallization  only  when  dried  in  vacuum  to  100°  for  24  hours.  An 
iodomethylate  was  prepared  by  treating  d-lupanine  in  methylalcoholi* 
solution  with  methyliodide.  From  the  mono-iodomethylate  the  cor- 
responding gold  and  platinum  salts  were  prepared. 

Other  bases  could  not  beJound  in  the  seeds. 

Arch.  d.  Pharm.  1904,  242. 

Morphine.  C.  Reichard  has  found  the  following  color  reactions 
for  morphine:  On  warming  some  morphine  or  its  sulphate  with  a 
little  sulphuric  acid  to  which  some  sodium,  arsenite  sodium  arsenate, 
antimony  trichloride  or  stannous  chloride  had  been  added  a  perman- 


48 

ent  red  color  is  produced.  Several  other  alkaloids  tried  did  not  give 
this  reaction. 

On  adding  a  trace  of  morphine  or  any  of  its  salts  to  a  concent- 
rated solution  of  bismuth  chloride  an  intensely  yellow  color  is  pro- 
duced. Many  other  alkaloids  also  give  color  reactions  with  bismuth 
chloride  but  these  are  more  or  less  different  from  the  morphine 
reaction.  Atropine  also  gives  a  yellow  color  with  bismuth  chloride 
but  the  color  disappears  on  warming  the  liquid. 

Cocaine  gives  no  color  reaction  with  bismuth  chloride  unless 
strong  sulphuric  acid  be  present  but  even  then  the  color  disappears 
on  warming  the  liquid. 

With  a  very  dilute  solution  of  cobalt  nitrate,  morphine  gives  no 
color  whatever,  but  in  presence  of  concentrated  sulphuric  acid  a  deep 
red  or  brown-red  color  is  produced  which  slowly  changes  at  first  to 
a  yellowish-red  and  then  to  a  very  permanent  brownish-yellow. 

Atropine  gives  with  cobalt  nitrate  in  the  absence  of  strong  sul- 
phuric acid  a  grass  green  color. 

With  cerium  dioxide  (obtained  by  heating  cerium  nitrate)  and 
sulphuric  acid  morphine  gives  on  standing  at  ordinary  temperature 
a  blue  violet  color.  Atropine  and  cocaine  do  not  give  the  reaction. 
Brucine  brought  in  contact  with  cerium  dioxide  and  sulphuric  acid 
in  the  cold  gives  a  reddish  or  a  reddish-yellow  color  which  after  a 
short  while  changes  to  an  intense  yellow.  Chem.  Ztg.,  28,  p.  1102. 

L.  Knorr  continues  his  investigations  on  the  constitution  of 
morphine.  It  is  known  that  the  three  alkaloids  morphine,  codeine 
and  thebaine  are  derivatives  of  8,  4,  6 — trioxyphenanthrene  (See  this 
Review  1904  Prog,  in  Alk.  Chem.  during  1903) 

/\ 
HO/  *    \ 

3  1 

HO\ 

\/        \ 

I  I 

/\  I    / 
/        \/ 

I5  I 

H()|6 

\  .     / 


Trioxyphenanthrene. 


49 

but  the  question  about  the  form  of  linking  and  the  function   of  the 
so  called  indifferent  oxygen  atom  has  not  yet  been  cleared  up. 

We  are  also  as  yet  in  the  dark  with  regard  to  the  way  in  which 
the  group  —  CHa.CEk.N.CHs  —  which  is  eliminated  from  thebaine  and 
codeinone  in  the  form  of  ethanol  methylamine,  HO.Ctl2.CH2.NH.CH3, 
by  means  of  acetic  anhydride  is  linked  to  the  partially  reduced 
phenanthrene  nucleus. 

The  following  experiments  help  to  bring  us  nearer  to  the  solution 
of  these  problems. 

When  «-methylniorphimethine  (OH)(CH80)Ci7Hi6ON.CH3  is  de- 
composed by  means  of  hydrochloric  acid  (Ber.  Dtsch.  Chern.  27,  1147) 
there  is  formed  among  other  products  a  basic  substance  /?-chlorethyl- 
dimethylamine,  C1.CH2.CH2.N(CH3)2.  The  base  itself  could  not  be 
isolated  but  on  distilling  the  basic  part  of  the  reaction  products 
with  sodium  hydroxide  compounds  are  obtained  which  are  identical 
with  those  obtained  by  distillation  with  alkali  of  /3-chlorethyldi- 
methylamine  made  synthetically,  namely,  tetramethylethylenediam'ine, 
(CH3)2N.CH2.CH2.N(CH3)2,  and  ethanoldimethylamine,  OH.CH2.CH2.- 
N(CH3)2. 

In  order  to  separate  these  two  bases  the  distillate  is  acidulated 
with  hydrochloric  acid  and  concentrated  to  a  small  bulk.  On  now 
adding  absolute  alcohol  most  of  the  hydrochloride  of  tetrarnethyl- 
ethylenediamine  is  precipitated  in  small  crystals.  After  separating 
these  crystals  by  nitration  the  filtrate  is  treated  with  picric  acid 
which  precipitates  the  rest  of  the  tetramethylethylenediamine  as  an 
insoluble  picrate.  The  nitrate  'from  this  picrate  is  acidulated  with 
sulphuric  acid  and  the  picric  acid  removed  by  shaking  out  the  liquid 
with  ether. 

The  liquid  is  now  made  alka.line  with  sodium  hydroxide  and  the 
ethanoldimethylamine  distilled  over  with  steam  into  dilute  hydro- 
chloric acid.  From  the  acid  solution  the  ethanoldimethylamine  is 
isolated  in  the  form  of  its  crystalline  chloraurate. 

On  heating  /3-methylrnorphimethine  with  alooholic  sodium  ethylate 
to  150°  the  base  is  decomposed  into  methylmorphol  and  dimethyl- 
aminoethylether,  (CH3)2N.CH2.CH2O.CH2.CH3.  A  small  amount  of 
dirnethylamine  is  also  formed  at  the  same  time.  As  a-methylmor- 
phimethine  is  converted  into  the  isomeric  ^-modification  by  the 


50 

action  of  sodium  ethylate  and  codeine  iodomethylate  is  changed  by 
the  same  reagent  into  a-methylmorphimethine  we  can  use  for  the 
preparation  of  the  dimethylaminoethylether  either  one  of  the  two 
methylmorphimethines  or  codeine  iodomethylate. 

The  dimethylaminoethylether  is  an  oily  liquid  which  can  be  freed 
from  water  by  means  of  potassium  hydroxide  and  boiling  with 
barium  oxide.  It  forms  a  chloraurate,  a  picrate  and  an  iodomethyl- 
ate, (Cfi3)3l.N.C2H4O.C2H5?  (ethylether  of  cholinehydriodide). 

On  heating,  thebairie  iodomethylate  with  sodium  ethylate  for  a 
few  minutes  thebaol  (dioxyphenanthrene  dimethyl  ether)  and  tetra_ 
methylethylenerliamine  are  formed.  More  prolonged  heating  resinifies 
the  subsance. 

v 

This  decomposition  of  thebaine  iodomethylate  can  also  be  effected 
by  heating  it  with  alcohol  alone  to  160° — 165°,  but  under  these  con- 
ditions dimethylamine  is  also  formed.  Similar  decomposition  pro- 
ducts are  formed  by  heating  codeinone  iodomethylate  under  pressure1 
with  alcohol,  only  instead  of  thebaol,  3,  — methoxy  — 4,  6  — dioxy- 
phenanthrene is  produced. 

This  easy  decomposition  of  the  iodomethylates  of  thebaine  and 
codeinone  shows  that  the  side  chain  C.C.N,  in  these  substances  is 
easily  split  off.  The  greater  stability  of  codeinone  iodomethylate  is 
due  to  the  fact  that  codeine  contains  a  tetrahydrophenanthrene  ring 
whereas  in  thebaine  there  is  a  dihydrophenanthrene  ring. 

.It  is  evident  that  the  dimethylaminoethylether  is  not  a  primary 
product  in  the  above  reaction.  It  could  not  also  be  formed  from 
ethanoldirnethylainine  because  hydramines  cannot  be  converted  into 
ethers  by  alcohol  or  sodium  ethylate.  We  must  therefore  suppose 
that  the  chain  C.C.N  is  split  off  as  an  unsaturated  vinyldimethyl- 
amine,  (CHs^N.CHrCH^,  group.  Such  a  group  could  be  easily  con- 
verted by  the  action  of  alcohol  into  dimethylaminoethylether,  by  the 
action  of  acetic  anhydride  into  the  acetate  of  dimethylaminoethanol 
and  in  the  presence  of  dimetylamine  into  tetramethylethylenediamine. 

If  this  supposition  should  prove  to  be  correct  the  formula  of 
morphine  will  have  to  be  changed  so  as  to  show  that  the  indifferent 
oxygen  atom  is  not  a  member  of  an  oxazine  ring  as  is  generally 
supposed  but  is  linked  in  the  same  way  as  in  morphenol. 


51 


\x  • . 

/OH 

\/ 

Mor  phenol. 

With  regard  to  the  C.C.N  group  we  would  have  to  assume  that  it 
is  present  in  morphine  in  the  form  of  a  reduced  pyrroline  ring  or  a 
reduced  pyridine  ring. 

It  would  of  course  be  difficult  to  account  for  the  great  facility 
with  which  this  ring  complex  is  split  off  from  the  molecule  unless  we 
assume  that  the  paradihydro  system  behaves  somewhat  like  quinones 
in  which  the  groups  generally  have  great  mobility. 

Ber.  Dtsch.  Chem.  Ges.  1904,  3494. 

Nicotine.  C.  S.  Hudson  has  investigated  the  miscibility  of  ni- 
cotine with  water  at  different  temperatures. 

The  conctraction  and  evolution  of  heat  which  take  place  upon 
mixing  nicotine  with  water  and  the  dependence  of  the  specific  rota- 
tion and  the  refraction  equivalent  of  the  alkaloid  upon  the  concen- 
tration of  its  solution  seem  to  indicate  the  formation  of  a  hydrate. 
The  formation  of  such  a  hydrate  would  also  explain  why  nicotine  is 
miscible  with  water  in  all  proportions  only  at  certain  temperatures. 
Below  60°  and  above  210°  nicotine  and  water  are  miscible  with  each 
other  in  all  proportions.  Solutions  containing  less  than  7.8  per 
cent  or  more  than  82  per  cent  of  nicotine  remain  homogeneous  at 
all  temperatures.  A  solution  containing  7.8  percent  nicotine  be- 
comes turbid  at  89°  and  clear  again  at  150°.  Below  90°  the  upper 
layer  is  richer  in  water,  above  90°  the  lower  layer  is  richer  in  water 
and  at  90°  the  two  layers  interchange  places. 

Zeitschr.  phys.  Chem.  47,  113. 

Papaverine.  II.  Pschorr  in  collaboration  with  M.  Stahlin  and 
M.  Silberbach  have  succeeded  in  converting  papaverine  into  an  iso- 
quinoline  derivative  of  phenanthrene  which  is  very  nearly  related  to 
apomorphine. 


52 

The  relationship  between  papaverine  and  apomorphine  is  shown 
by  their  structural  formulae: 

CH2       N  CH2       N.CH3 
X>        X\       S\                                        /\       X\       X\ 
CH3.OX        \X                     \CH                             X  \CHa 

I  I  |\H       | 

CH3.O\       X          X\       XQH  H0\  /CH2 

\X          X       \X  \X       \/       \X 

HO  | 

CH3.O\        X 

\x  \x 

O.CH3 
Papaverine  Apomorphine 

(i)     :!  (ii) 

It  seemed,  therefore,  possible  to  convert  amidopapaverine  into  a 
derivative  of  apomorphine  by  the  same  method  by  which  ortho- 
amidostilbene  derivatives  are  con  verted  into  phenanthrene  derivatives, 
i.  e.,  by  converting  the  amido  into  a  diazo  compound  and  then  con- 
densing the  two  benzol  rings  of  the  molecule  through  the  elimination 
of  the  the  NH2  group : 


Orthoamidostilbene  Pheuanthrene 

(III)  (IV) 

Hence  an  attempt  was  made  to  convert  orthoainidopapaverine 
into  an  isoquinoline  derivative  of  phenanthrene  by  eliminating  the 
ainido  group  and  condensing  the  two  benzol  rings  of  the  molecule 

CH2      N  CH2       N 

X\        /\        S\  X\       X\       J\ 

CH3.O/        \X  \CH  CHs.O/        \/  \CH 

II 

N 


CH3.0\        /NH2  /\        /CH 

\/        /     \/  \/     \x      \x 

CH3.0| 
CH3.O\        /  \ 

XX  \X 

O.CHa  O.CHs 

Orthoainidopapaverine.  laoquinoline  derivative  of  pbenanthreiie. 


53 


The  orthoamidopapaverine  pas  prepared  from  orthonitropapa- 
verine  in  which  the  orthoposition  of  the  nitro  group  was  proven  by 
the  fact  that  upon  oxidation  of  its  iodomethylate  (V)  it  gave  sym- 
metrical nitro veratric  acid  (VI)  and  by  treatment  with  alkali  it  gave 
6-nitro-3,  4-dimethoxy toluol  (VI)  and  6,  7-dimethoxy-N-methyliso- 
quinoline  (VII). 


CH2 


N: 


/\ 
€H8.OX 

I 


CHs.OX        /N02    /\ 


CH3 


I 

\CH 


/CH 


CH3.O/ 
3 


CH.«0\         / 
\/ 
O.CHs 

Orthonitropapaverineiodomethylate. 

(V) 

C02H 
/     (CH3) 


N.CHs 
/\ 

XCH 


/\ 


CHs.OX    5   /NOa 


Symemtrical  nitro  veratric  a.cid  and 
6-nitro-3,  4-dimethoxy  toluol. 

(VI) 


CH.a.OX        / 

\s 

O.CH3 

6,  7-Dimethoxy-N-methyliso- 
quinoliiie. 

(VII) 


The  reduction  of  the  ortho-nitropapaverine  to  the  corresponding 
amido  derivative  presented  no  difficulties  but  it  was  found  impossible 
to  eliminate  the  amido  group  and  thus  condense  the  two  benzol 
rings  of  the  molecule  by  diazotizing  the  amido  compound  and  then 
boiling  the  diazo  compound  with  powdered  copper.  It  would  seem 
that  the  diazo  compound  easily  loses  the  elements  of  water  and  is 
converted  into  an  anhydride  from  which  the  nitrogen  atom  cannot 
be  split  off 


54 


CH2 


N« 


/\       /       \      //\ 
CH3.0/       \/HO  \CH 

i     S     i 


CH3.0\        XN 


N/\       /CH 

\.  I 


\/ 

O.CH.3 


CH8.0/ 
CH3.0\ 


Diazo  compound. 
(VIH) 

CH\ 

\        /\     \ 
\/        \N  \X 

\ 


\CH 
/CH 


I 

CH3.0\ 


\X 


XOCHS 


Anhydride. 

(IX) 

An  attempt  was  then  made  to  avoid  the  formation  of  this 
anhydride  by  taking  orthonitropapaveraldine  (XI)  instead  of  ortho- 
nitropapaverine  and  thus  eliminating  the  influence  of  the  CHo  group. 
But  it  was  found  that  by  reduction  in  acid  solution  of  orthonitro- 
papaveraldine a  substance  was  formed  which  had  the  formula 
CooHis^Os  and  showed  neither  the  reactions  of  a  ketone  nor  those 
of  a  primary  amine.  It  is  probable  that  the  reduction  takes  place 
in  the  same  way  as  in  the  formation  of  methylanthranil  (X)  from 
orthonitroacetophenone. 

CO.CHs  C.CHj 


/\ 


\ 


\/        \NO2 
O.Nitroacetophenone. 


Methylanthranil. 

(X) 


O.CH3 
Orthonitropapaveraldine. 

(XI) 


CH8.O, 


/\ 


\CH 


CH8.0\        / 


Anthranilopapaverine. 

(XII) 

The  substance  was  therefore  named  anthranilopapaverine. 

If  the  reduction  of  o.nitropapaveraldine  be  carried  out  by  means 
of  ammoniumsulphide  the  reaction  takes  a  normal  direction  and 
o.amidopapaveraldine  is  obtained.  But  on  trying  to  diazotize  the 
amido  compound  and  then  split  off  the  diazo  group  it  was  found 
impossible  to  isolate  a  definite  compound.  Though  the  product  ob- 
tained by  boiling  the  diazo  compound  with  water  was  crystalline  it 
was  almost  perfectly  black  and  could  not  be  purified. 

After  these  unsuccessful  attempts  the  formation  of  a  phenanthrene 
derivative  of  isoquinoline  was  at  last  accomplished  by  starting 
with  o.amidotetrahydro-N-methylpapaverine.  On  reducing  o.nitro- 
papaverine  chloromethylate  both  the  nitro  group  and  the  isoquino- 
line complex  of  the  molecule  are  reduced  with  the  formation  of 
o-amidotetrahydro-N-methylpapaverine.  On  diazotizing  this  amido- 
compound  and  then  treating  with  powdered  copper  in  the  cold  the 


56 

desired  phenanthrene  derivative  was  obtained.    It  was  characterized 
in  the  form  of  its  crystalline  iodomethylate. 

The  formation  of  the  phenanthrene  derivative  from  the  amido- 
N-methyltetrahydropapaverine  can  be  expressed  as  follows: 

CH2       CH2      NCH3 

/\       /\       /\ 

\CH2 
!  \H      I 


CH2 
CHs.O/ 

CH3.0\        / 
\/ 

CH2       N.CHs 
/\        /\ 
\CH2 
|\H      | 

NH2  /\        /CH2 
/        \/              > 
1 

-. 

-; 
\        / 

\        s 

\/ 

O.CHs 

CH3.O\ 


CH3.O\ 

\x 

O.CH3 

O.Amido-tetrahydro-N-methyl-  Phenanthreno-N-inethyl-tetra- 

papaverine.  hydropapaverine. 

(XIII)  (XIV) 

Experimental.  —  The  orthonitropapaverine  was  obtained  in 
almost  theoretical  yield  by  adding  papaverine  under  constant  stir- 
ring- to  nitric  acid  at  a  temperature  of  — 5°  — 0°  and  then  throwing- 
the  liquid  into  ice  water.  The  crystalline  nitrate  of  o.nitropapa- 
verine  thus  obtained  is  warmed  with  ammonia  on  the  water  bath  till 
the  whole  mass  is  converted  into  the  free  base. 

On  treating  the  o.nitropapaverine  with  methyliodide  in  chloro- 
formic  solution  at  100°  the  iodomethylate  was  obtained.  In  the 
same  way  the  bromomethylate  can  be  made  substituting  methyl- 
bromide  for  methyliodide. 

For  the  preparation  of  the  chloromethylate  of  o.nitropapaverine 
the  latter  was  converted  into  the  methylsulphate -methylate, 
C2oH2o06N2\cH3SO4>  b3r  means  of  dimethylsulphate  in  chloroformic 
solution  and  then  decomposing  the  quaternary  methylsulphate 
methylate  in  hot  concentrated  aqueous  solution  with  a  strong  solu- 
tion of  potassium  chloride.  By  substituting  potassium  iodide  or 
potassium  bromide  for  pocassium  chloride  the  above  mentioned 
iodomethylate  and  chloromethylate  of  o.nitropapaverine  can  be  ob- 
tained. 

On  oxidizing  the  iodomethylate  of  o.nitropapa.verine  with  hot 
potassium  permanganate  symmetrical  6-nitroveratric  acid  (VI)  was 
formed. 


CM 

On  wanning  the  iodomethylate  with  potassium  hydrate  6-nitro-3, 
4-dimethoxy  toluol  (VI)  separated  out.  From  the  mother  liquor  of 
the  latter  6,  7-dimethoxy-N-methylisoquinoline  (VII)  was  obtained 
by  adding  strong  hydrochloric  acid  in  which  the  isoquinoline  deriva- 
tive is  difficultly  soluble. 

The  orthoamidopapaverine  was  prepared  by  reducing  the  o.nitro- 
papaverine  ia  alcoholic  solution  witth  stannous  chloride  dissolved  in 
strong  hydrochloric  acid  and  precipitating  the  amine  with  excess  of 
alkali.  The  o.amidopapaverine  crystallizes  with  one  molecule  of 
alcohol  of  crystallization  which  is  partially  given  off  at  ordinary 
temperature. 

The  amidopapaverine  was  diazotized  in  the  usual  way  but  the 
solution  soon  deposited  a  yellow  gelatinous  mass  without  evolution 
of  nitrogen.  From  the*  salt  of  the  diazo  compound  the  free  base 
was  liberated  by  ammonia  and  recrystallized  from  alcohol.  The  sub- 
stance was  undoubtedly  the  anhydride  of  diazopapaverine  corre- 
sponding to  formula  (IX). 

If  the  freshly  prepared  solution  of  the  diazopapaverine  be  treated 
in  the  cold  with  powdered  copper  nitrogen  is  evolved  and  the  liquid 
assumes  a  red  color.  From  the  red  liquid  ammonia  precipitates  a 
red  amorphous  substance  which  could  not  be  purified. 

An  iodomethylate  of  the  diazopapaverine  was  prepared  by  means 
of  methyliodide  in  chloroformic  solution  at  100°.  The  iodomethylate 
contains  one  molecule  of  water  of  crystallization  which  it  loses  only 
when  heated  in  vacuum. 

The  methylsulphate  methylate  of  diazopapaverine  is  formed  on 
digesting  diazopapaverine  with  dimethylsulphate  in  chloroformic 
solution  and  precipitating  the  methylsulphate  methylate  with  ether. 

Potassium  iodide  in  hot  concentrated  solution  converts  the 
methylsulphate  methylate  into  the  above  mentioned  iodomethylate 
of  diazopapaverine. 

Unlike  the  iodomethylate  of  nitropapaverine  (V)  the  iodo- 
methylate of  diazopapaverine  is  not  decomposed  by  warm  potassium 
hydrate  but  there  is  simply  a  replacement  of  the  halogen  atom  by 
an  OH  group. 

Orthonitropapaveraldine  was  prepared  by  two  different  methods : 
either  by  nitrating  papaveraldine  or  by  oxidizing  nitropapaverine. 
The  papaveraldine  was  prepared  by  oxidizing  papaverine  with 


58 

potassium  dichromate  in  glacial  acetic  acid  solution  and  purified  by 
solution  in  benzol  and  precipitation  with  petroleum  ether. 

On  treating  papaveraldine  with  nitric  acid  and  throwing  the 
liquid  into  water  the  nitrate  of  o.nitropapaveraldine  is  precipitated. 

The  same  compound  was  obtained  by  oxidizing  o.nitropapaverine 
with  sodium  dichromate  in  boiling  glacial  acetic  acid. 

The  reduction  of  o.nitropapaveraldine  obtained  by  either  of  the 
above  methods  to  anthranilopapaverine  (XII)  was  carried  out  by 
means  of  stannous  chloride  and  hydrochloric  acid  in  alcoholic  solu- 
tion. The  substance  shows  neither  the  reactions  of  a  ketone  nor 
those  of  an  amine. 

If  the  reduction  of  o.nitropapaveraldine  be  effected  by  passing 
a  current  of  sulphuretted  hydrogen  into  a  boiling  alcoholic  solution 
of  the  nitro  compound  in  presence  of  ammonia  the  reduction  takes 
a  normal  direction  and  o.aniidopapaveraldine  is  formed.  The  latter 
was  purified  by  solution  in  hydrochloric  acid  and  precipitation  with 
ammonia. 

An  attempt  to  diazotize  the  o.aniidopapaveraldine  in  presence  of 
strong  sulphuric  acid  resulted  in  the  formation  of  a  sulphonic  acid, 


Orthoamidopapaveraldine  was  found  to  form  two  series  of  salts: 
With  very  dilute  acids  intensily  red  solutions  are  obtained  but  with 
strong  acids  the  solutions  are  yellowish-green  and  become  red  upon 
addition  of  water. 

On  diazotizing  the  o.arnidopapaveraldme  a  substance  was  ob- 
tained which  evolves  nitrogen  at  60°  with  the  formation  of  black 
needle  shaped  crystals  which  could  not  be  purified. 

On  reducing  tne  chloromethylate  of  nitropapaverine  with  tin  and 
hydrochloric  acid  the  tin  double  salt  of  amidopapaverine  is  formed 
at  first  but  on  boiling  the  liquid  for  two  hours  the  compound  is 
further  reduced  and  the  tin  double  salt  of  N-methyltetrahydroamido- 
papaverine  (XIII)  separates  out.  The  double  salt  was  decomposed 
by  means  of  sulphuretted  hydrogen,  the  excess  of  EbS  removed  by 
a  current  of  air  and,  after  adding  some  sodium  sulphite  (to  prevent 
oxidation),  the  N-methyltetrahydropapaverine  precipitated  with  a 
saturated  solution  of  potassium  carbonate. 

The  compound  forms  soluble  salts  with  hydrochloric,  sulphuric 
and  nitric  acids  and  reduces  silver  nitrate  solutions  even  in  the  cold. 

The  preparation    of   the   looked    for   phenanthrene  derivative 


(XIV)  was  carried  out  by  diazotizing  the  N-methyltetrahydro- 
papaverine  in  presence  of  dilute  .sulphuric  acid  and  heating 
the  resulting  sulphate  of  the  diazo  compound  with  powdered 
copper.  When  the  evolution  of  nitrogen  ceased  the  phenanthreno- 
X-methyltetrahydropapa,verine  (XIV)  was  precipitated  by  ammonia 
in  a  semisolid  condition.  On  dissolving  the  phenanthrene  derivative 
in  chloroform  and  evaporating  off  the  solvent  the  compound  was 
left  in  the  form  of  a  reddish-brown  syrupy  liquid  which  could  not  be 
made  to  crystallize.  It  was  analyzed  after  converting  it  into  the 
crystalline  iodomethylate  by  means  of  methyliodide  in  alcoholic 
solution.  Ber.  Dtsch.  Chem.  Ges.  1904,  1927. 

M.  Freund  and  H.  Beck  have  tried  to  reduce  papaveraldine  in 
the  expectation  that  after  taking  up  four  atoms  of  hydrogen  papa- 
veraldine could  be  converted  by  means  of  methylation  and  then 
splitting  off  the  dimethoxybenzoyl  group  into  a  substance  similar 
to  hydrohydrastinine  or  hydrocotarnine 

O.CH3 

/\  - 

CH3.O/  CH3.O/ 

I 

\ 
\/  ,  \/ 

CO  CO 

I        7>  I 

/\      /v  /\      /\ 

CHs.O/        \/'      XN  CH8.0/        \/    |    \NH 

I  I      H      I 

i  I  I  I  !  I 

CHa.OX        /\        /CH  CHa.OX        /\        /CH2 

\/        \/  \/        \/ 

(<\\  CH2 

Papaveraldine  or  tetrametlioxy- 
benzoylisoqninoline. 

CH2 

/\        /\ 
()  /  \N.CH3 

CH<    j  | 

O\        /\        /CH2 
\/        \> 

GHa 

Hvdrohvdrastinine. 


60 

It  was  found  that  on  reducing  papaveralcline  electrolytically  the 
substance  took  up  six  instead  of  four  atoms  of  hydrogen  one  atom 
of  oxygen  going  out  at  the  same  time  as  water.  The  new  compound 
is  isomeric  but  not  identical  with  tetrahydropapaverine.  It  was 
therefore  named  isotetrahydropapaverine.  It  has  the  formula 
C2oH2oN04  or  possibly  (CsoH^NCXOo  and  could  not  be  obtained  in 
crystalline  form.  It  was  purified  by  converting  it  into  its  nitroso 
derivative.  It  forms  a  hydrochloride  and  a  hydriodide. 

On  heating  the  nitroso  derivative  with  alcoholic  hydrochloric 
acid  it  was  reconverted  into  isotetrahydropapaverine. 

With  methyliodide  the  base  gave  a,  compound  which  seemed  to 
be  the  hydriodide  of  methylisotetrahydropapaverine. 

The  physiological  effect  of  the  hydrochloride  of  the  base  is  simi- 
lar to  that  of  cocaine.  Ber.  Dtsch.  Chern.  Ges.  1904,  3321. 

H.  Decker  and  0.  Klauser  have  investigated  the  constitution  of 
the  alkylhalides  of  papaverine. 

By  the  action  of  alkali  upon  these  alkylhalides  Stransky  (Monats- 
hefte  f.  Chem.  1888,  751)  obtained  compounds  which  he  considered 
to  be  derivatives  either  of  papaverinium  hydroxide  (I)  or  of  the 
anhydride  of  this  hydroxide  formed  through  the  elimination  of  one 
molecule  of  water  from  two  molecules  of  the  hydroxide 

/\       /\ 
CH3.O/  \        OH 

'!        i        i.y 

|N.CH2.CeH5 
CH3.O\        /  > 

\/ 


O.CH3 
N-Benzylpapaveriniumhydroxide. 

(I). 

According  to  Glaus  and  Kassner  these  compounds  contain  one 
molecule  water  less  than  is  required  by  the  formulae  of  the  hydrox- 
ides. They,  therefore,  think  that  these  compounds  are  derived 
through  the  elimination  of  one  molecule  of  water  from  one  molecule 
of  the  hydroxide  with  the  formation  of  nlkylidene  compounds  (II) 


/\       /\ 
CHa.Q/ 

!          I  I 

I          I  i 

(,'Ha.O\        /\       ^ 
\/        \# 

CH2 


\ 
O.CH« 


O.CH;., 
Benzylidenepapaverine. 

(ID 

The  authors  find  that  in  accord  with  Clans'  statement  these  ether 
soluble  compounds  really  contain  one  molecule  water  less  than  the 
corresponding  papaverinium  hydroxide  derivatives  and  that  they 
are  derived  not  from  two  but  from  one  molecule  of  the  base.  This 
was  shown  by  an  estimation  of  the  molecular  weight  of  the  N-methyl 
derivative  of  papaverine  (V). 

As  to  the  constitution  of  these  compounds  the  authors  consider 
them  to  be  derivatives  of  a  hypothetical  base  isomeric  with  papa- 
verine named  isopapaverine 


CHa.O 

i 
NIT 


/ 

\x 
II 
CH 


'O.CH3 
O.CH;! 
Isopapaverine. 


Tliis  supposition  is  supported  by  the  experience  of  the  authors 
with  derivatives  of  isoquinoline,  the  parent  substance  of  papaverine. 
It  was  shown  in  a  previous  paper  (Journ.  f.  pr.  Chem.,  1893,  38) 
that  the  compounds  obtained  by  the  action  of  alkali  upon  the 
iodomethylate  of  isoquinoline  quickly  change  from  the  ammonium 
form  to  the  carbinol  form  (III).  This  was  shown  by  the  fact  that 
the  base  can  be  oxidized  to  N-methylisoquinolone  (IY)  whose  con- 
stitution was  established  by  the  synthesis  of  Bamberger  and  Frew 
(Ber.  Dtsch.  Chem.  Ges.  1894,  20ft) 


N.CHa 


Ammonium  base.  Carbinol  form.  N-MethylisoquinolonK. 

(Ill)  (IV) 

In  the  same  way  the  ammonium  form  of  alkyl  papaverine  (V) 
which  is  formed  at  first  is  supposed  to  be  transformed  into  the  car 
binol  form  (VI)  in  the  next  step 


N.CHa 


|\OH 
CH8 

I 


\/O.CH2 

O.CHrj 


Carbinol  base. 

(VI) 


63 

As  these  carbinol  bases  of  papaverine  are  tertiary,  not  secondary 
like  !}he  isoquinoline  compounds,  the  papaverine  bases  cannot  be 
changed  into  isoquinolone  compounds  but  are  transformed  into  iso- 
papaverine  derivatives,  i.  e.,  (VI)  changes  to  (VII). 


X\     XN.C 


N.CHs 


/O.CHs 
O.CHs 


N-methylisopapaverine. 
(VII) 

The  correctness  of  this  view  was  shown  by  the  fact  that  N-benzyl- 
isopapaverine  can  be  oxidized  to  a  derivative  of  N-benzylisoquino- 
lone.  The  oxidation  takes  place  according  the  following  scheme: 


CH3.0/ 


/\         XN.C7H7 
\/         \/ 

,'!« 
I 


I  I 

\         /O.CH3 
\/ 
O.GH3 

N-Benzylisopaparerine 
(VIII) 


/\      /\  /\/\ 

CH3.O/    §  \./    *  \  HO/       \/        \ 

«  SI  > 

CH3O\         X\     i    /N.C7H7         H0\         /\         /N.C7H7 

\/         \/  \/        \/ 

A  A 

Dirnetoxybenzylisoquinolone.      Dioxybenzylisoquinolone. 

(IX)  (X) 

CO.OH 

I 
/\ 


COM 

1 


\ 

O.CH3 
MethylrapJHn, 


j  I 

\  /'O.CH3 

Veratric  acid. 


The  reconversion  of  the  tertiary  alkylisopapaveriues  into  .salts 
qf  quaternary  papaverinium  bases  by  means  of  acids  can  be  explained 
by  assuming*  that  at  first  a  salt  of  the  tertiary  base  is  formed  which 
soon  changes  to  a,  salt  of  the  quaternary  papaverinium  base,  i.  e., 
the  grouping  (XJ)  changes  to  the  grouping  (XII) 


CH:5  CH8 

/-H  | N/ 

\C1  ,/     \ 


c 


CH  CH2 

I  ,  I 

(XI)  (XII) 


The  observation  of  Claus  and  his  co-workers  that  the  yellow 
ajkylisopapaverines  when  dissolved  in  water  form  colorless,  strongly 
alkaline  solutions  of  papaverinium  hydroxides  (VII  -  — >  V)  from 
which  upon  concentration  the  isopapaverines  again  separate  out 

(V >  VII)    can    be   explained    by    assuming    that    this '  reversible 

transformation  is  either  of  the  same  nature  as  the  formation  of  salts 

(XI >  XII)  or  that  there  is  at  first  an  addition  of  the  elements 

of  water  to  the  double  binding  with  the  formation  of  the  carbinol 
base  (VIII  -  — >  VI)  which  then  changes  to  the  ammonium  form 
(VI >V). 

We  have  here  then  a  new  case  of  formation  of  a  free  quaternary 
base  from  a  free  unsaturated  tertiary  base  through  the  addition  of 
water.  Till  now  the  only  method  of  transformation  of  tertiary  into 
quaternary  bases  has  been  by  passing  through  the  salt  of  the 
quaternary  base  (Hofmann's  method). 

The  derivation  of  the  alkylpapaverines  from  isopapaverine  which 
has  a  quinoid  double  linking  would  also  account  for  the  yellow  color 
of  these  bases. 

Transformations  similar  to  those;  of  the  alkylpapaveriues  wen? 
observed  by  K.  Brunner  (Monatshefte  f.  Chein.  21,  156)  in  the  in- 
dolium  bases.  These  transformations  can  be  explained  in  the  same 
way  as  those  of  the  isopapaverine  derivatives.  From  this  analogy 
of  behaviour  of  the  isoquinoline  derivatives  and  those  of  the  indo- 
line  series  the  conclusion  can  be  drawn  that  this  behaviour  is 


05 

characteristic  of  all  cyclo-ainmoniuni  bases  having  an  alkyl  substitu- 
tion group  in  a-position. 

Experimental.  N-Methylisopapaverine  (VII)  was  prepared  by 
heating  papaverine  with  methyl  iodide  to  100°  for  six  hours  and  re- 
crystallizing  the  iodoinethylate  thus  obtained  from  water.  The  free 
N-methylisopapaverine  can  be  obtained  from  this  iodomethylate  by 
adding  alkali  to  its  ac^ueons  solution. 

If  to  a  dilute  solution  of  the  iodomethylate  (0.6%)  a  few  drops 
of  alkali  be  added  and  the  liquid  shaken  up  with  benzol  the  latter 
assumes  a  yellow  color.  On  adding  more  alkali  the  aqueous  liquid 
also  becomes  yellow  and  when  the  amount  of  alkali  reaches  15  to 
18  per  cent  a  thick  yellow  crystalline  precipitate  of  N-methyliso- 
papaverine is  formed  which  disappears  again  upon  addition  of  water 
the  liquid  becoming  colorless. 

This  yellow  precipitate  is  not  pure  N-methylisopapaverine  but 
contains  some  unchanged  iodomethylate  and  probably  also  some  of 
the  carbinol  base  (VI).  The  N-methylisopapaverine  can  be  purified 
by  dissolving  it  in  water  and  precipitating  with  a  30%  solution  of 
sodiurnhydroxide.  It  forms  yellow  transparent  crystals  melting  at 
129°— 131°.  It  is  deliquescent  in  the  air  absorbing  carbon  dioxide 
and  water.  The  aqueous  solution  of  N-methylisopapaverine  is  color- 
less and  has  a  strong  alkaline  reaction.  Upon  concentration  of  the 
solution  or  addition  of  alkali  the  yellow  isopapaverine  base  is  pre- 
cipitated. Acids  convert  the  isopapaverine  base  quantitatively  into 
salts  of  methylpapaverine.  Picric  acid  converrs  the  N"-methyliso- 
papaverine  into  a  picrate  which  is  identical  with  N-methylpapa- 
verine  picrate  (XI  to  XIJ). 

An  ethylisopapaverine  was  obtained  which  is  even  less  stable  and 
more  deliquescent  than  the  methyl  compound.  With  even  very  little 
water  the  ethyl  compound  forms  a  yellow  caustic  solution  of  ethyl- 
papa  veriniumhydroxide  from  which  the  yellow  isopapaverine  is  re- 
precipitated  upon  the  addition  of  alkali  or  concentration  of  the 
liquid.  From  a  benzol  solution  of  the  isobase  the  ammonium  base 
can  be  removed  by  shaking  with  water. 

Quantitative  titrimetric  estimations  of  the  partition  of  the  base 
between  benzol  and  water  showed  that  with  the  increase  of  the  dilu-t 
tion  of  the  aqueous  solution  the  ratio  of  the  amounts  taken  up  by 
the  two  immiscible  solvents  increases  in  favor  of  the  water.  For  this 
reason  the  presence  of  alkali  which  diminishes  the  number  of  ious 


66 

and  the  tendency  of  formation  of  hydrates  displaces  the  quotient  in 
the  opposite  direction,  i.  e.,  in  favor  of  the  benzol. 

N-Benzylisopapaverine  (VIII)  is  obtained  more  easily  than  the 
methyl  compounds.  Even  the  addition  of  only  two  and  a  half  per 
cent  of  sodium  hydroxide  to  a  solution  of  papaverine  benzylchloride 
precipitates  the  yellow  isobase  in  crystalline  form  and  once  formed 
the  isobase  is  only  slowly  reconverted  into  the  ammonium  base  by 
water.  It  would  seem  that  with  the  increase  in  the  molecular  weight 
of  the  N-substitution  groups  the  equilibrium  -is  displaced  in  favor  of 
the  isobase.  Hence  while  metli37lisopapaverine  is  alkaline  even  to 
phenolphtalem,  benzylisopapaverine  is  alkaline  only  towards  litmus 
but  not  towards  phenolphtalein. 

N-Benzylisopapaverine  shows  the  phenomenon  of  auto-oxidation 
with  the  intermediate  formation  of  superoxides  as  oxygen  carriers. 
On  passing  air  through  a  one  per  cent  solution  of  the  benzyl  com- 
pound in  presence  of  a  small  amount  of  alkali  the  odor  of  methyl- 
vanilin  is  developed,  and  after  a  few  days  about  90%  of  the  theo- 
retical amount  of  6,  7-dimethoxy-N-benzyl-l-isoquinolone  is  formed 

(VIII >  IX).  In  the  mother  liquor  small  amounts  of  veratric 

acid  can  be  found. 

The  dimethoxybenzylisoquinolone  forms  an  orange-red  picrate 
which  upon  recrystallization  from  alcohol  is  decomposed  into  its 
components  coloring  the  solution  yellow.  The  picrate  is  probably 
not  a  salt  of  the  tertiary  base  but  simply  a  moleculor  addition  com- 
pound in  which  the  picric  acid  is  attached  to  the  benzol  ring. 

By  means  of  hydrochloric  acid  the  dimethoxybenzylisoquinolone 

was  converted  into  the  corresponding  dioxy  compound  (IX >X). 

The  free  dioxybase  was  obtained  by  passing  carbon  dioxide  into  its 
alkaline  solution.  The  base  gives  no  color  reactions  with  ferric 
chloride.  From  dilute  solutions  in  alkalies  the  alkaline  salts  are 
precipitated  by  concentrated  alkalies. 

The  methyl  and  ethylisopapaverine  are  also  capable  of  auto- 
oxidation.  Ber.  Dtsch.  Chem.  Ges.  1904,  520. 

H.  Decker  and  his  collaborators  have  prepared  several  derivatives 
of  isopapaverine  (see  proceeding  paragraph).  Some  of  these  are 
derived  from  isopapaverine  itself  while  others  are  derivatives  of 
monobromisopapaverine.  The  isopapaverine  derivatives  were  ob- 
tained by  the  action  of  alkalies  upon  the  corresponding  papaverininm 
compounds : 


1.  Quaternary  papaverinium  Halts.  —  Papaverine  n-butylbromide, 
('UtHgoOiNBr,   was  prepared  from  its  components  by  heating  them 
to   100°  for  12  hours.    It    is    a  crystalline  powder  containing  two 
molecules  of  water  of  crystallization.    It  melts  first  at  109°,  then 
becomes  solid  on  further  heating  and  decomposes  at  217°. 

Alkalies  convert  the  n-butylbromide  compound  into  n-butyl-iso- 
papaverine  which  has  a  yellow  color  and  is  difficult  to  crystallize. 
Hydrochloric  acid  converts  the  n-butylisopapaverine  into  papa- 
verinium chlorobutylate  from  which  were  obtained  a  picrate,  a  mer- 
cury salt  and  a  chloroplatinate. 

Papaverine  iodoisobutylate,  Ca-iHaoC^NI,  was  prepared  by  the 
same  method  as  proceeding  compound.  From  its  solutions  alkalies 
precipitate  the  corresponding  yellow  isobase. 

Papaverine-para-nitrobenzylchloride,  C27H2706N;>C1,  was  obtained 
by  heating  the  components  to  140°  for  six  hours  in  an  open  vessel , 
then  dissolving  the  product  in  alcohol  and  precipitating  it  with  ether. 
It  is  difficultly  soluble  in  water  and  forms  a  picrate  and  a  mercury 
salt. 

Addition  of  alkali  to  this  paranitrobase  does  not  liberate  the 
isobase  but  the  alkaline  liquid  soon  assumes  a  red  eolor  which  after 
a  while  changes  'to  black  indicating  a  deeper  decomposition.  The 
same  reaction  is  produced  even  by  ammonia. 

A  papaverine  iodoisopropylate  could  be  obtained  only  in  small 
amount  and  with  great  difficulty. 

2.  Monobrompapaverine,  C2oH2oO4NBr,  was  prepared  by  adding 
bromine  with  constant  stirring  to  a  mixture  of  papaverine  and  strong 
hydrochloric  acid.    It  forms  small  needles  easily   soluble   in  water. 
Dilute  alkalies  d<5  not  split  off  hydrobromic  acid    from    the  brom- 
papaverine  showing  that  the  bromine  atom  is  not  attached  to  the 
methylene  group  of  the  alkaloid. 

On  heating  brompapaverine  with  methyliodide  N-metbylbrom- 
papaveriniumiodide  was  obtained. 

Treated  with  dimethylsulphate  brompapaverine  gives  an  addition 
compound  which  is  converted  by  sodiumhydroxide  into  N-methyl. 
bromisopapaverine  (I) 


G8 

/\       X\ 
CHs.O/ 

I  I  I 

I  I  I 

CH8.0\        /\        /  N.CH.-j 

\/        \/ 

li 

CH 


/         \ 
fir" ! 

\        /  O.CHs 
\/ 

O.CHg 

(I) 

This  brominated  isopapaverine  base  is  much  more  stable  than 
the  corresponding  nonbrominated  isopapaverine,  The  brominated 
compound  reacts  only  slowly  with  waterforming  brompapaverinium 
methyl  hydroxide  (II). 


/\       /\ 
CH3.0/       \/        \        CH3 

I  IN/ 

I          I          !    \ 

CH3.O\       /\  OH 

\/        \/ 

CH2 


| 

\        XO.CHs 
\/ 

O.CHs 


(ID 


When  brompapaverine  is  heated  with  benzylchloride  to  120°— 130° 
for  four  hours  an  addition  compound  is  formed  which  is  converted 
by  sodiumhydroxide  into  N.benzylbromisopapaverine  (III) 


I 
I 

N.CHa.Cellr, 


CH 
I 

/\ 

/        \ 
Br-| 

I  I 

\        /  O.CHs 
\/ 
O.CHa 

(HI) 

The  brominated  benzylisopapaverine  base  is  also  much  more 
stable  than  the  corresponding  nonbrominated  compound. 

The  N-Benzylbromisopapaverine  base  is  only  slowly  affected  by  the 
oxygen  of  the  air,  but  potassium  permanganate  (&%)  quickly  oxid- 
izes it  to  N-benzyl-6,  7-dimethoxy-a-isoquinolone  (IV)  and  6-brom- 
veratric  acid  (V) 

CO.OH 

/\       /\  | 

CH«.O/    •"   ^V    *  \  /\ 

|0  3|  /    'I     \ 

IT  2|  Br~-|«          2| 

CH3.O\        /\    i   /N.CH2C6H5  |5          B| 

\/        \/  \        /O.CHs 

il  \/ 

O  O.CHs 

(IV)  (V) 

If  less  potassium  permanganate  be  taken  in  this  reaction  there 
seems  to  be  formed  instead  of  the  bromveratric  acid  6-bromveratric 
aldehyde  (VI)  * 

COH 

/\ 
/       \ 


O.CH 

(VI) 


TO 

Experiments  with  nitropapaverihe  showed  that  the  alkylhalides 
of  nitropapa verine  are  not  converted  by  alkalies  into  isopapaverine 
bases  but  into  various  decomposition  products. 

It  would  seem,  therefore,  that  whereas  the  bromine  atom  makes 
the  isopapaverine  bases  more  stable,  the  nitro  group  to  the  contrary 
greatly  diminishes  their  stability. 

Ber.  Dtsch.  Cliera.  Ges.  1904,  3809. 

Pepper.  Contrary  to  the  statement  of  W.  Johnstone  (Chem. 
News  1888,  58,  235),  R.  Kayser  could  not  detect  any  volatile  alka- 
loid supposed  by  Johnstone  to  be  piperidine  in  pepper.  On  distilling 
pepper  with  steam  the  distillate  was  found  to  be  perfectly  neutral. 

On  distilling  pepper  with  magnesium  oxide  some  ammonia  was 
formed  which  was  identified  by  the  properties  of  the  hydrochloride 
and  the  chloroplatinate.  Zeitschr.  offentl.  Chem.  1904,  137. 

Pilocarpine.  Et.  Barrall  describes  some  new  color  reactions  of 
pilocarpine: 

1.  On  heating  pilocarpine  with  a  solution  of  sodium  persulphate 
the  liquid  becomes  yellow,  emits  a  narcotic  and  slightly  ammoniacal 
odor  and  blackens  mercurous  nitrate. 

2.  On  heating  a  pilocarpine  solution  with    sulphuric   acid    and 
some  formic  aldehyde  the  liquid  passes  through  the  following  colors : 
yellow,  yellowish,  brown,  blood-red  and  red-brown. 

3.  Mandelin's  reagent  when  heated  with  a  very  dilute  solution 
of  pilocarpine  assumes  first  a  yellow  color,  then  turns  slowly  light 
green    and   at   last   becomes    light   blue.     The    latter   color   is  not 
changed  by  dilution  with  water. 

4.  On  heating  a  solution   of  pilocarpine  with    a   one   per   cent 
solution  of  potassium  permanganate  in  sulphuric  acid  the  liquid  at 
first  becomes  colorless  and  then  assumes  a  dark  yellow  tint  emitting 
an  odor  resembling  that  of  burned  sugar. 

Journ.  Pharm.  Chim.  XIX,  188. 

Quinine.  J.  B.  Ballandier  has  investigated  some  color  reactions 
of  some  alkaloids. 

QUININE  AND  QUINIDINE.  When  a  moderately  acid  solution  of 
quinine  or  quinidine  is  treated  with  bromine  vapors  the  fluorescence 
of  the  liquid  disappears.  If  one  drop  of  a  copper  sulphate  solution 
and  one  drop  ammonia  water  be  then  added  to  the  liquid  the  latter 
assumes  a  peach  flower  color  which  on  adding  more  ammonia 


changes  first  to  violet  and  then  to  green.  If  acid  be  now  added  to 
the  liquid  the  color  becomes  either  blue  or  violet  according  to  the 
amount  of  acid  added. 

On  adding  ammonia  alone  to  a  solution  of  quinine  previously 
treated  with  bromine  vapors  the  thalleioquin  reaction  is  developed. 
If  to  the  liquid  be  then  added  a  drop  of  a  copper  sulphate  solution 
the  liquid  assumes  a  dark  blue  color  which  is  not  destroyed  by  excess 
of  mineral  acids. 

CHELIDONINE.  A  solution  of  guajacol  in  concentrated  sulphuric 
acid  gives  a  beautiful  carmine-red  color  with  chelidonine. 

CHELIDONINE  AND  NARCEINE.  Tannin-sulphuric  acid  gives  a  green 
color  with  chelidonine  and  narceine. 

Journ.  Pharm.  Chim.  20,  151.. 

E.  Leger  has  investigated  Andre's  reaction  for  quinine  which 
consists  in  treating  the  solution  of  a  quinine  salt  successively  with 
chlorine  water  or  bromine  water  and  ammonia.  The  author  finds 
that  the  color  obtained  varies  with  the  amount  of  bromine  and 
water  added.  In  some  cases  the  liquid  even  remains  colorless.  It  is 
therefore  necessary  to  carry  out  the  reaction  always  under  the  same 
conditions. 

Working  under  definite  conditions  it  is  even  possible  to  apply 
Andre's  reaction  to  the  quantitative  evaluation  of  cinchona  bark. 

Journ.  Pharm.  Chim.,  XIX.  281. 

Further  work  by  E.  Leger  upon  Andre's  reaction  for  quinine  (see 
proceeding  paragraph)  has  shown  that  the  reaction  cannot  be  made 
use  -of  for  the  quantitative  evaluation  of  cinchona  bark. 

Journ.  Pharm.  Chim.  XIX,  484. 

H.  Carette  has  investigated  the  composition  of  several  neutral 
hydrochlorides  of  quinine. 

1.  A  neutral  hydrochloride  containing  two  and  a  half  molecules 
of  water  of  crystallization. 

This  was  obtained  by  dissolving  one  molecule  of  anhydrous 
quinine  in  two  molecules  hydrochloric  acid  largely  diluted  with  water 
and  concentrating  the  liquid  on  the  waterbath. 

This  hydrochloride  forms  fine  radiated  crystals  which  begin  to 
melt  at  80°,  become  brown  at  215°  and  melt  to  black  liquid  at  a 
higher  temperature. 

The  salt  is  hygroscopic  but  does  not  liquify  unless  exposed  to  a 
very  moist  atmosphere.  In  dry  air  at  a  temperature  of  20°  the 


crystals  lose  a  small  part  of  their  water  of  crystallization.  At  102° 
all  the  water  of  crystallization  is  removed  the  salt  assuming'  a 
yellowish  tint  which  disappears  on  cooling.  There  is  no  loss  of 
hydrochloric  acid  at  this  temperature. 

2.  A  neutra.l  hydrochloride  containing  one  and  a  half  molecules 
of  alcohol  of  crystallization.    This  salt  is  obtained  by  recrystallizing 
neutral  quinine  hydrochloride  from  an  alcoholic,  solvent  containing 
either  30,  55  or  95  per  cent  alcohol. 

The  salt  foriris  large  transparent  crystals  which  become  yellow 
at  165°— 170°  and  liquid  at  180°— 185°.  The  alcohol  is  almost 
completely  removed  on  keeping  the  salt  in  vacuum  at  ordinary 
temperature. 

The  dry  salt  assumes  a  yellowish  tint  on  exposure  to  light.  The 
crystallized  salt  is  soluble  in  one  part  of  alcohol  (95yr).  When  the 
salt  is  exposed  to  the  air  it  loses  its  alcohol  of  crystallization  and 
takes  up  two  and  a  half  molecules  of  water  instead. 

3.  A  neutral  hydrochloride  containing  half  a  molecule  of  water 
of  crystallization.    This  salt  is  obtained  by  exposing  the  salt  men- 
tioned sub  2)  to  a  temperature  of  35°  to  40°.    At  this  temperature 
the  salt  loses  all  its  alcohol  of  crystallization  and  takes  up  half  a 
molecule  of  water. 

This  salt  is  the  most  stable  of  the  series  taking  up  moisture 
much  more  slowly  than  either  the  salt  obtained  by  removing  the 
water  of  crystallization  from  the  salt  sub  1)  or  the  salt  obtained  by 
removing  the  alcohol  from  the  salt  sub  2). 

4.  A    hydrochloride    containing    three    molecules    of    water   of 
crystallization.    This  salt  is  obtained  by   exposing   the   anhydrous 
salt  obtained  either  from  1)  or  2)  to  a  very  damp  atmosphere.    In 
an  atmosphere  saturated  with  moisture  the  salt  becomes  liquid. 

The  specific  rotation  of  anhydrous  quinine  hydrochloride  was 
found  to  be  au  = — 233°.  Journ.  Pharrn.  Chim.  XX,  347. 

According  to  C.  Erba  quinine  hydrochloride  when  recrystallized 
from  alcohol  does  not  contain  one  and  a  half  molecules  of  alcohol 
(see  proceeding  paragraph)  but  one  molecule  alcohol  and  one  mole- 
cule water.  Journ.  Pharm.  Chim.  XX,  550. 

Ricinine.  Maquenne  and  Philippe  have  investigated  the  con- 
stitution of  ricinine.  The  alkaloid  was  prepared  by  exhausting  the 
deoleated  seeds  with  hot  water,  concentrating  the  liquid  to  small 
volume,  adding  then  a  mixture  of  alcohol  and  chloroform  and  after 


73 

distilling1    oft'    the    solvent    recrystallizing    the    residue   from    boiling- 
water.    One  kg.  of  the  seeds  yielded  about  2  grams  of  alkaloid. 

Kicinine  has  a  very  bitter  taste,  is  difficultly  soluble  in  all  sol- 
vents and  crystallizes  in  thin  plates  melting  at  201°.  Its  formula 
was  found  to  be  CsHs^C^. 

On  saponifying  ricinine  with  potassium  hydroxide  a  molecule  of 
methyl  alcohol  is  split  off  and  ricininic  acid  is  formed.  . 

C8H8N202  +  H20  =  CH3.OH  +  C7H6N202 

Ricininic  acid. 

Recininic  acid  crystallizes  from  water  in  shining  needles  difficultly 
soluble  in  water  or  alcohol  and  is  decomposed  without  melting  at 
about  320°  (on  the  bloc  Maquenne). 

On  heating  ricininic  acid  with  fuming  hydrochloric  acid  to  150° 
carbon  dioxide  and  ammonia  are  liberated  and  the  hydrochloride  of 
a  new  base  is  formed 


C7H6N202  +  2H20  =  C02  +  NH3  +  C6H7N02 

This  new  base  crystallize*  in  needles  containing  one  molecule  of 
water  of  crystallization  and  is  almost  completely  insoluble  in  ice 
water.  Crystallized  it  melts  at  80°,  anhydrous  it  melts  170°—  171°. 
It  is  a,  very  weak  base,  colors  ferric  chloride  red  and  forms  nitro 
and  bromine  derivatives.  It  is  supposed  to  have  the  constitution 
of  a,  methyl  dioxypyridine  or  a  methyl  oxypyridone 

C.OM  CO 

•lit1/       \C.O1I  HC/        XC.OH 


CH  CH3-C\        /CH 
\    '  \/ 

N  NH 

Metliyldioxypyridine.  Methyloxypyridone. 


Ricininic  acid  seems  to  be  imino-«-picoliiae  carboxylic    acid   and 
ricinine  the  methyl  ester  of  ricininic  acid. 


74 

NH 


CHX 
CH3-C\        yC-CO.OH  CHa-CV       />  C-CO.O.CH3 


Ricininic  or  imino-  Ricinine  or  methyl 

a-picoline  carboxylic  acid.  ester  of  ricininic  acid. 

Bull.  Soc.  Chim.,  Paris  1904,  466. 

Further  work  by  L.  Maquenne  and  L.  Philippe  on  methyloxypyri- 
done  obtained  from  ricinine  (see  proceeding  paragraph)  shows  that 
methyloxypyridone  is  a  very  weak  base,  though  it  is  capable  of  form- 
ing salts  with  hydrochloric,  and  phosphoric  acids  and  combining 
with  platinum  tetra-chloride.  Towards  phenolphtalein  it  behaves 
even  like  a  monobasic  acid.  It  is  neutral  towards  helianthin  and 
its  reaction  towards  litmus  is  indefinite.  Tt  reduces  Fehling's  solu- 
tion in  the  heat  and  does  not  react  with  hydroxylamine  or  phenyl- 
hydrazine.  It  forms  a  mono-,  di-  and  tribromine  derivatives  which 
are  all  easily  soluble  in  alcohol,  have  a  decided  acid  reaction  and 
are  slowly  decomposed  by  hot  water  but  quickly  by  potassium 
hydroxide  with  the  elimination  of  bromine. 

On  evaporating  methyloxypyridone  with  nitric  acid  (sp.  grav.  1, 
2)  a  nitro  derivative,  CoHeNOsCNOa)  is  formed  which  crystallizes  in 
yellow  needles,  has  a  strong  acid  reaction  forming  definite  salts  with 
salifiable  bases  and  is  very  difficultly  soluble  in  hot  water.  The 
calcium  salt  of  nitromethyloxypyridone  (C6H5N204)Ca  +  5H2<J  cry- 
stallizes in  fine  needles  and  is  easily  soluble  in  water. 

The  ammonium  and  potassium  salts  are  also  crystalline. 

On  heating  the  hydrochlorfde  of  methyloxypyridone  with  phos- 
phorus peutachioride  to  160°  two  substances  are  obtained  of  which 
one  is  solid,  the  other  liquid.  The  solid  compound  boils  at  98° 
under  a  pressure  of  18  mm.  and  has  a  composition  of  a  dichlorpyri- 
dine,  CsHsClsN.  As  one  methyl  group  is  split  off  in  this  reaction 
the  methyl  group  in  methyloxypyridone  and  hence  also  in  ricinine 
must  be  attached  to  the  nitrogen  atom,  not  to  carbon  as  was  pre- 
viously supposed  (see  preceeding  paragraph). 

The    dichlorpyridine  was  converted    into    pyridine    by  means  of 


T5 

hydriodic    acid   and   rod   phosphorus  and   the  pyridine  identified  by 
converting  it  into  its  double  salt  with  mercuric  chloride. 

From  these  results  the  conclusion  is  drawn  that  ricinine  and  its 
decomposition  product  methyloxypyridone  have  the  following  con- 
stitution : 

C        ~  N  CO 

/\        /  /\ 

HCV        \C  HC/        XC.OH 


HC\        /C— COa.CF-h  HC" 


/CH 


\/  ,      \/ 

N.CHg  N.CHs 

Ricinine.  Methyloxypyridone. 

The  exact  position  of  the  side  chains  in  ricinine  is  as  yet  of 
course  unknown. 

The  acidity  of  methyloxypyridone  which  is  increased  by  the  intro- 
nuction  of  bromine  or  the  nitro  group  is  accounted  for  by  the  presence 
of  the  CO  and  OH  groups  in  the  molecule. 

Compt.  Rendus,  139,  No.  21,  2iSme  semestre  840. 

Skimmianiiie.  J.  Honda  has  isolated  a  poisonous  alkaloid 
from  the  leaves  of  Skimmia  Japonica  Thunb. 

The  cut  leaves  were  extracted  repeatedly  with  96%  alcohol  at 
ordinary  temperature,  the  alcohol  distilled  off  and  the  residue  taken 
up  with  warm  water  and  filtered.  The  aqueous  liquid  was  made 
alkaline  and  shaken  out  with  chloroform.  After  distilling  off  the 
chloroform  the  alkaloid  was  left  in  yellowish  columns  melting  at 
175.5°.  The  base  hardly  has  any  taste  but  the  salts  are  bitter.  It 
is  soluble  in  alcohol  and  chloroform  but  insoluble  in  water  or  petro- 
leum ether.  The  solutions  of  the  alkaloid  have  a  neutral  reaction 
towards  litmus.  Dilute  mineral  acids  convert  the  alkaloid  into  salts 
only  when  the  acids  are  in  excess  and  upon  concentration  of  such 
acid  solutions  the  salts  crystallize  out  in  needles.  If  the  excess  of 
acid  in  solutions  of  the  alkaloid  be  neutralized  with  an  alkaline  car- 
bonate or  the  alkaloidal  salts  be  treated  with  alkohol  or  water  the 
free  base  separates  out. 

The  alkaloid  is  precipitated  by  most  alkaloidal  reagents.  It  forms 
a  chloroplatinate  and  an  unstable  chloraurate.  Concentrated  sul- 
phuric acid  dissolves  the  alkaloid  with  brownish-yellow  color.  Addi- 


tion  of  potassium  chlorate  to  the  sulphuric  acid  gives  a  red-brown 
color.  Froede's  reagent  gives  first  a  green  and  then  a  blue  color. 
A  solution  of  potassium  permanganate  in  sulphuric  acid  gives  first 
a  violet  and  then"  a  brown-yellow  colors.  Concentrated  nitric  acid 
colors  skimmianine  first  yellow,  then  orange-red. 

The  formula  of  skimmianine  was  found  to  be,  GsaHaeNgOo. 

Arch.  f.  exp.  Pathol.  Pharmak,  52,  83. 

Sparteine.  M.  Scholtz  and  P.  Pawlicki  have  made  some  ex- 
periments in  order  to  determine  whether  the  two  nitrogen  atoms  of 
sparteine  have  the  same  functions  or  not. 

If  one  nitrogen  atom  is  "more  basic  than  the  other  then  alkyl 
halides  ought  first  to  attach  themselves  to  that  nitrogen  atom 
which  is  more  basic  in  preference  to  the  other  one.  Hence  if  two 
different  alkylhalides  be  made  to  act  upon  sparteine  one  after  the 
other  we  ought  to  get  isomeric  but  not  identical  substances  when 
the  order  in  which  the  alkylhalides  are  taken  is  made  to  vary. 

Experiments  showed  that  by  taking  first  methyliodide  and  then 
ethyl  iodide  we  really  get  a  substance  that  is  isomeric  but  not 
identical  with  the  substance  obtained  by  taking  first  ethyliodide  and 
then  methyliodide.  The  same  was  found  to  be  true  with  methyl- 
iodide  and  the  methyl  ester  of  iodo  acetic  acid  or  witn  benzyliodide 
and  the  methyl  ester  of  iodo  acetic  acid. 

On  treating  sparteine  with  methyl  iodide  in  presence  of  methyl 
alcohol  at  100°  the  hydriodide  of  sparteine  methyl  iodide, 
CijFHaeNaJCHsI.HI,  was  obtained,  showing  that  the  methyl  alcohol 
also  takes  part  in  the  reaction  furnishing  hydriodic  acid  by  acting 
upon  part  of  the  methyliodide. 

By  the  action  of  ammonia  upon  this  salt  sparteine  methyliodide, 
Ci5H26N2.CH3I,  was  obtained  identical  with  the  sparteine  methyl- 
iodide  previously  obtained  by  Bamberger  by  the  action  of  methyl- 
iodide  upon  sparteine  in  absence  of  methyl  alcohol. 

No  separation  of  free  sparteine  was  noticed  in  this  action  of 
ammonia  upon  the  hydriodide  of  sparteine  methyliodide  (compare 
Bamberger,  Ann.  Chem.  Pharm.  235,  376). 

On  heating  sparteine  methyliodide  with  ethyliodide  sparteine 
methyliodide  ethyliodide,  CisHaeNsCOHsIXCsHRl)  was  obtained.  The 
compound  crystallizes  in  plates  melting  at  239°. 

On  reversing  the  order  of  the  alkyliodides  the  isomeric  compound 


77 

was  obtained  in  octoliedric  crystals  melting-  at  246°.  In  the  same 
way  it  was  found  that  the  compounds  obtained  from  ben zyl iodide 
and  methyliodoacetate  used  in  different  order  differed  from  each 
other  in  crystalline  form  and  melting  point.  The  same  was  also  true 
of  methyliodide  and  methyliodoacetate. 

When  sparteine  hydriodide  is  treated  with  methyliodide  the  same 
hydriodide  of  sparteine  methyliodide  is  obtained  which  is  formed 
from  sparteine  and  methyliod'ide  in  presence  of  methyl  alcohol  at 
100°.  The  compound  has  the  formula  Ci5H2GN2.CH3LHl.  As  in  the 
compound  obtained  by  the  first  method  the  CHsI  group  must  be 
linked  to  the  less  basic  nitrogen  atom  the  same  must  be  true  of  the 
compound  obtained  by  the  second  method.  But  as  Bamberger  (loc. 
cit.)  has  previously  shown  that  in  the  cold  the  action  of  methyl- 
iodide  upon  sparteine  in  presence  of  alcohol  consists  in  the  formation 
of  sparteine  methyliodide  not  the  hydriodide  of  the  latter,  we  must 
assume  that  at  first,  i.  e.,  in  the  cold  the  CHy!  group  attaches  itself 
to  the  more  basic  nitrogen  atom  and  that  only  by  heating  the  mixture 
to  100°  hydriodic  acid  is  formed  by  the  action  of  the  alcohol  upon 
the  methyliodide  giving  the  hydriodide  of  sparteine  methyliodide. 
Hence  in  the  second  method  when  we  start  with  sparteine  methyl- 
iodide,  which  must  contain  tne  CHsI  group  attached  to  the  more 
basic  nitrogen  atom,  we  ought  to  get  the  hydriodide  of  sparteine 
methyliodide  in  which  the  CHgl  group  is  again  attached  to  the  more 
basic  nitrogen  atom.  In  other  words  the  hydriodides  of  sparteine 
methyliodide  obtained  by  the  two  different  methods  ought  to  be 
only  isomeric  but  not  identical  with  each  other.  But  as  they  are 
identical  it  must  be  assumed  that  in  one  of  the  two  methods  there 
is  an  internal  rearrangement  of  the  nitrogen  atoms. 

By  the  action  of  amyliodide  upon  sparteine  in  presence  of  alcohol 
the  hydriodide  of  sparteine  amyliodide,  CisH^eNa.CoHnl.HI,  wa,s 
obtained.  In  the  absence  of  alcohol  either  sparteine  monoamyliodide 
or  sparteine  diamyliodide  were  obtained  according  to  whether  one 
or  two  molecules  of  amyliodide  were  made  to  react  with  one  mole- 
cule of  sparteine. 

An  addition  compound  of  ortho  -  xylylene  dibromide, 
Ci5H26N2.C6H4(CH2Br)2,  was  obtained  by  the  action  of  ortho- 
xylylene  dibromide  upon  sparteine  in  chloroformic  solution.  It 
crystallizes  in  needles  melting  at  273°. 

Arch.  d.  Pharm.  1904,  513. 


78 

H.  \Vaekernagel  and  K.  \Yolfeiistein  liave  investigated  the  con- 
stitution of  sparteine.  They  find  that,  contrary  to  the  statements 
of  Ahrens.  sparteine  does  not  contain  a  CHa  — N  group,  does  not 
take  up  two  hydrogen  atoms  forming  a  dihydrosparteine  and  does 
not  form  a  dioxysparteine  when  oxidized  with  hydrogen  peroxide. 
The  oxidation  product  obtained  by  oxidizing  sparteine  with  hydrogen 
peroxide  must  belong  to  the  group  of  amino  oxides  containing  oxygen 
doubly  linked  to  nitrogen  as  in  the  group  =N=0.  This  is  shown 
by  the  fact  that  this  oxidation  product  unlike  sparteine  but  like  all 
amino  oxides  is  insoluble  in  ether  and  that  it  is  very  easily  reducible 
back  to  sparteine. 

The  presence  of  a  pyrrol  ring  in  sparteine  was  shown  by  the 
vapors  of  the  decomposition  products  of  the  alkaloid  reddening  pine 
wood  moistened  with  hydrochloric  acid. 

From  all  the  investigations  of  sparteine  carried  out  both  by  the 
authors  themselves  and  other  investigators  the  authors  draw  the 
following  conclusions  about  the  constitution  of  the  alkaloid : 

There  must  be  in  sparteine  a  combination  of  a  piperidine  and  a 
pyrrol  ring. 

The  alkaloid  does  not  contain  unsaturated  groups;  both  nitro- 
gen atoms  are  tertiary  and  neither  is  attached  to  a  methyl  group. 

There  must  be  at  least  four  ring  systems  in  the  alkaloid.  This 
follows  from  the  ratio  of  carbon  to  hydrogen  in  the  formula  of  the 
base,  CisH26N2.  As  the  boiling  point  of  sparteine  seems  to  be  too 
low  for  a  four  ringed  compound  it  is  very  probable  that  there  is  in 
sparteine  a  combination  of  two  bicyclic  rings,  possibly  two  norhydro- 
tropidine  rings  linked  together  by  a  methylene  group. 

Ber.  Dtsch.  Chem.  Ges.  1904,  3238. 

Strychnine.  D.  Martin  has  made  some  bromine  derivatives  of 
strychnine. 

Monobromstr37chnine,  CaiHsiBr^Os,  was  made  by  adding  a 
solution  of  bromine  in  strong  hydrobromic  acid  (50%)  to  a  solution 
of  strychnine  in  dilute  hydrobromic  acid  in  presence  of  sodium  acetate 
till  the  precipitate  at  first  produced  did  not  soon  redissolve  and  then 
precipitating  the  brominated  alkaloid  with  ammonia.  The  mono- 
bromstryclmine  melts  at  199°,  is  easily  soluble  in  alcohol  and  acidu- 
lated water  but  difficultly  soluble  in  chloroform,  ether  or  acetone. 
It  combines  with  methyliodide  and  ethyliodide  and  forms  a  per- 


79 

bromide,  Cj^I^iBrNaOe.HBr.Br  when  treated  with  a  solution  of 
bromine  in  hydrobromic  acid. 

The  perbromide  melts  at  204°  and  loses  its  perbromine  when  dis- 
solved in  organic  solvents.  It  is  stable  in  the  dark  but  resinifies 
when  exposed  to  the  light. 

On  further  brominating  the  monobromstrychnine  a  dibromstry- 
strychnine,  C 2iHsoBr ^N 2Q2,  was  obtained,  The  dibromcompound 
melts  at  130°— 131°,  forms  addition  products  with  methyliodide  and 
ethyliodide  and  a  perpromide,  C2iH2oBr2N2,02.HBr.Br,  which  loses 
bromine  upon  solution  in  acetone. 

A  periodide  of  monoiodostryclmine  hydriodide  C2iH2iIN202.HI.I 
was  obtained  by  boiling  a  solution  of  strychnine  in  excess  of  dilute 
sulphuric  acid  with  iodic  acid  and  then  destroying  the  excess  of  iodic 
acid  by  means  of  a  little  hydrobromic  acid.  The  periodide  melts  at 
154°,  is  insoluble  in  water  or  dilute  acids  and  dissolves  in  acetone 
with  separation  of  iodine. 

A  diiodo  addition  product,  C2iH22N2O2.l2,  was  made  by  adding 
a  solution  of  iodine  in  hydriodic  acid  in  presence  of  sodium  acetate. 
It  is  insoluble  in  water  and  loses  all  its  iodine  upon  solution  in 
acetone. 

A  monoiodostryclmine,  Ci>iH2iIN202,  was  prepared  by  pouring 
an  acetone  solution  of  monoiodostryclmine  hydriodide  periodide  into 
dilute  ammonia.  The  compound  melts  at  188°  and  is  soluble  in 
dilute  acids.  Bull.  Soc.  Chim.  Paris,  1904,  386. 

C.  Minunni  and  F.  Ferrulli  have  investigated  some  reactions  of 
tetrachlorstrychnine.  The  tetrachlorstrychnine  was  prepared  by 
treating  a  solution  of  strychnine  in  glacial  acetic  acid  with  chlorine. 
It  differs  from  strychnine  in  that  it  gives  an  oxime  when  treated 
with  hydroxylamine  showing  the  presence  of  a  CO  group  whereas 
strychnine  itself  not  giving  an  oxime  does  not  contain  such  a 
CO  group.  In  the  formation  of  the  tetrachlorstrychnine  there 
seems  therefore  to  be  an  intramolecular  change  which  probably 
consists  in  the  transformation  of  a  grouping  CH^C.OH  into  a 

grouping  CH2  — CO.  The  two  hydrogen  atoms  in  the  last  grouping- 
are  probably  replaced  by  chlorine  in  the  tetrachlorine  derivative. 

On  passing  chlorine  into  a  solution  of  strychnine  in  glacial  acetic 
acid  the  hydrochloride  of  tetrachlorstrychnine,  C2!H]7CUN2O2.HC1. 
+  2H20  soon  separates  out.  It  is  insoluble  in  all  organic  solvents 


so 

but  can  be  recrystallized  from  hot  glaci.il  acetic  acid.  The  hydro- 
chloride  crystallizes  in  small  white  crystals  containing  two  molecules 
of  water  of  crystallization,  becomes  brown  at  about  200°  but  does 
not  melt  even  at  200°.  The  water  of  crystallization  could  not  be 
estimated  because  the  substance  on  heating  loses  hydrochloric  acid. 

The  free  tetrachlorstrychnine  can  be  obtained  by  adding-  ammonia 
and  much  water  to  a  solution  of  the  hydrochloride  in  alcphol.  Its 
formula  is  C2iHisCl4N:>O2  +  H2O.  It  forms  a  flocculent  precipitate 
which  can  be  recrystallized  from  hot  alcohol.  Jt  is  also  soluble  in 
acetic  ether  and  warm  benzol.  It  becomes  brown  at  140°  and  melts 
with  decomposition  at  165° — 170°. 

A  hydrazone  of  tetrachlorstrychnine,  CoiHi8CloN2O(N— NH.CcHs), 
was  prepared  by  heating  an  alcoholic  solution  of  the  free  base  with 
phenylhydrazine  hydrochloride  and  then  adding  an  alcoholic  solution 
of  sodium  acetate.  The  hydrazone  forms  minute  crystals  which  a.iv 
easily  soluble  in  hot  alcohol  and  hot  benzol  but  difficultly  soluble  in 
ether.  It  becomes  dark  when  heated  but  does  not  melt  even  up  to 
260°. 

While  strychnine  itself  contains  no  hydrogen  that  is  replaceable 
by  acid  radicals  there  are  two  such  hydrogen  atoms  in  tetrachlor- 
strychnine.  By  heating  the  fcetrachlorstrychnine  hydrochloride  with 
acetic  anhydride  for  three  hours  morioacethyl  tetrachlorstrychnine, 
C2jHi7Cl4N202.CHa.CO,  is  obtained.  It  is  soluble  in  acetic  ether, 
benzol  or  alcohol.  It  becomes  brown  at  100°  and  melts  at  180° — 
197°. 

A  monobenzoyl  derivative,  C2iHi7CUN202(C6Hr>.CO)  was  ob- 
tained by  treating  the  hydrochloride  of  tetrachlorstrychnine  with 
benzoylchloride  in  pyridine  solution.  The  benzoyl  compound  becomes 
dark  at  about  220°  but  does  not  melt  even  up  to  260°.  It  is  diffi- 
cultly soluble  in  alcohol  or  ether,  but  easily  soluble  in  benzol,  acetic 
ether  or  glacial  acetic  acid. 

If  free  tetrachlorstrychnine  instead  of  its  hydrochloride  be  taken 
in  the  last  reaction  a  benzoyl  derivative  containing  one  molecule  of 
water  of  crystallization,  CoiHi7CUN202(C6H5.CO)  +  HaO,  is  formed. 
This  benzoyl  compound  is  soluble  in  bot  alcohol  from  which  it 
separates  out  on  cooling  in  light  yellow  crystals.  It  becomes  soft 
at  l:-U)°  and  melts  at  150°— in.")0. 

If  acetyl  chloride  be  made  to  act  upon  tot  raclilorsl  rvclinine  in 
pyndinc  solution  a  diacHyl  derivative  is  formed  but  there  is  at  the 


81 

same  time  an  elimination  of  one  molecule  of  hydrochloric  acid.  The 
diacetyl  compound  corresponds  therefore  to  formula  C2iHi5dsN202 
(CHa.COb.  It  is  soluble  in  acetic  ether,  alcohol  and  ether  and 
melts  with  decomposition  at  185°. 

A  dinitrotetrachlorstrychnine,  CoiHi6CU(NOi>)2N202,  was  obtained 
by  heating  the  hydrochloride  of  tetrachlorstrychnirie  with  strong 
nitric  acid  and  recrystalli/ing  the  product  from  alcohol.  It  is  soluble 
in  acetic  acid,  ether  or  alcohol.  It  becomes  brown  at  170°,  blackens 
at  1200°  but  does  not  melt  even  up  to  260°.  Tin  and  hydrochloric 
acid  reduce  the  dinitro  compound  to  a  colorless  reduction  product. 

In  preparing  tetrachlorstrychnine  as  described  above  there  are 
formed  besides  the  tetrachlorstrychnine  several  other  chlorine  deriva- 
tives of  the  alkaloid.  Of  these  only  a  hexachlorstrychnine  could  be 
isolated  in  pure  condition.  The  substance  is  very  difficultly  soluble 
in  all  organic  solvents  and  does  not  melt  up  to  260°. 

Gaz.  Chim.  Ital.  1904,  11,  364. 

C.  Reichard  finds  that  while  brucine  gives  characteristic  reactions 
with  mercury  or  silver  salts  (See  this  Review  page  117),  no  such  re- 
actions are  given  by  strychnine. 

When  a  solution  of  strychnine  nitrate  and  copper  nitrate  is  eva- 
porated to  dryness  the  residue  has  a.  deep  green  colored  rim.  Stan- 
nous  chloride  changes  the  color  to  violet  but  on  drying  the  green 
color  appears  again. 

If  instead  of  copper  nitrate  platinum  tetrachloride  be  used  the 
residue  when  moistened  with  sulphuric  acid  arid  warmed  becomes 
dark  red.  Brucine  treated  in  the  same  way  gives  a  yellow  color. 

When  treated  with1  hydrogen  peroxide  and  sulphuric  acid  strych- 
nine forms  a  blue  colored  liquid  with  a  yellow  rim.  On  standing  the 
whole  liquid  becomes  yellow.  The  yellow  substance  present  in  this 
liquid  is  insoluble  in  ether  so  that  when  the  liquid  is  shaken  up 
with  ether  the  latter  remains  colorless. 

On  warming  a  mixture  of  strychnine,  sulphuric  acid  and  titanic 
acid  a  blue  liquid  is  obtained  in  which  the  strychnine  crystals  can 
be  seen  to  assume  a  dark  color.  Addition  of  water  or  application 
of  heat  changes  the  color  to  yellow. 

Brueine  gives  the  same  reaction  but  the  addition  of  water  makes 
the  liquid  colorless. 


82 

When  strychnine  is  evaporated  with  some  potassium  hydroxide 
to  dryness  and  the  residue  moistened  with  a  solution  of  stannous 
chloride  a  light  blue  color  is  developed. 

Brucine  does  not  give  this  reaction. 

With  potassium  persulphate  or  ammonium  persulphate  and 
hydrochloric  acid  strychnine  gives  no  reaction  whatever  in  the  cold 
but  on  warming  the  liquid  assumes  a  yellow  color.  Brucine  with  the 
same  reagents  gives  a  beautiful  red  color  in  the  cold  and  the  color 
disappears  only  upon  prolonged  standing. 

The  last  reaction  can  be  used  to  distinguish  between  strychnine 
and  brucine.  Chem.  Ztg.  1901,  28,  977. 

Thebenine.  11.  Pschorr  and  C.  Massaciu  have  investigated  the 
constitution  of  thebenine  obtained  by  the  action  of  aqueous  hydro- 
chloric acid  upon  thebaine  or  codeinone  (See  this  Review  1904,  Prog. 
Alkal.  Chem.)-  As  thebenine  contains  CH2  less  than  thebaine  and  is 
a  secondary  base  while  thebaine  is  a  tertiary  base  Freund  (Ber. 
Dtsch.  Chem.  Ges.  3,  1357;  32,  168)  explains  the  conversion  of  the- 
baine into  thebenine  by  assuming  that  in  the  reaction  with  hydro- 
chloric acid  one  CHsO  group  of  thebaine  is  saponified,  i.  e.,  replaced 
by  an  OH  group  and  that  the  oxazine  ring  present  in  thebaine  (I) 
is  changed  to  a  furfurane  ring  in  thebenine. 


CH-.X 


H2.C/ 


/       \ 


\H 
/H 

\        / 

\/        \/ 

o 


O.CHs 


O.CHs 


Thebaine. 


(I) 


CHa.XFI-HC 


|.\H       | 
I/H 
/\        / 


O 


O.CHs 


OH 


Thebenine 


(II) 


These  formulae  for  thebaine  and  thebenine  satisfactorily  explain 
the  formation  of  triacetyl  thebenine  (III)  by  the  action 


/       \ 


O.CH3 


CH:!.CO 

I  /\ 

CH»— N-HC > 

i/H 

H2C\         C\        / 
\  \/ 

O.CHa.CO 


O.CHa.CO 


Triacetyl  thebenine 


(HI) 


84 


O.CH: 


OH 


Thebenol 

(IV) 


of  acetic  anhydride  upon  thebenine,  the  formation  of  tbebenol  (IV) 
from  thebenine  by  means  of  exhaustive  methylation,  the  formation 
of  methebenine  (V),  isomeric  with  thebaine,  by  the  methylation  of 
thebenine  and  the  conversion  of  this  methebenine  into  methebenol 
VI)  by  exhaustive  methylation. 


\ 


V      \ 

I 


CH3NH-HC  ---  /        \ 
I          ,  I\H      | 

I/B 

H2C\        /\        / 
\>        \X 

o 


O.CHg 


O.CH; 


Methebenine 

(V) 


8.1 


O.CHa 


\ 


\/ 

1 

i 

x\ 

H3C  — 

—  / 

\/ 

\H 

1 

/H 

1 

H3C\ 

/^ 

/ 

\/        \/ 

0 

Methebenol 

(VI) 

According  to  these  formulae  there  is  no  free  OH  group  in  methe- 
benine  (V)  and  of  the  three  oxygen  atoms  in  thebaine,  thebenine, 
thebenol,  methebenine  and  methebenol  one,  i.  e.,  the  oxygen  atom 
of  the  oxazine-or  the  fnrfurane  rings  is  linked  in  -the  same  way  as  in 
ethers  (bridge  oxygen). 

But  a  study  of  the  reactions  of  methebenine  by  the  authors 
shows  conclusively  that  there  must  be  an  OH  group  in  this  base. 
The  statement  of  Freund.  about  the  insolubility  of  methebenine  in 
alkalies  is  not  correct;  the  base  having  a  weak  phenolic  character 
simply  requires  a  large  amount  (about  six  molecules)  of  alkali  for 
solution.  From  concentrated  solutions  of  methebenine  hydrochloride 
potassium  hydroxide  precipitates  not  the  free  base  but  its  difficultly 
soluble  potassium  salt.  That  the  solubility  of  methebenine  in  alkali 
is  due  to  the  presence  of  an  OH  group  and  not  to  any  deep  change 
in  the  molecule,  e.  g.,  the  opening  of  an  oxygen  containing  ring, 
follows  from  the  fact  that  carbon  dioxide  precipitates  unchanged 
methebenine  from  its  solution  in  alkali  and  that  when  the  alkaline 
solution  of  methebenine  is  treated  with  hydrochloric  or  sulphuric 
acids,  the  same  salts  are  formed  which  are  obtained  by  the  action 
af  these  acids  upon  free  methebenine.  The  formation  of  a  diacetyl 
and  a,  dibenzoyl  derivative  by  means  of  cold  acetic  anhydride  or 
benzoyl  chloride  also  indicates  the  presence  of  an  OH  group  in 
methebenine. 

Hence  there  must  be  in  methebenine  an  OH  group  and  as  the 
other  two  oxygen  atoms  are  present  in  the  form  of  methoxyl  groups 


methebenine  cannot  contain  an   ''indifferent"    oxygen  atom    in    the 
form  of  an  oxazine  ring  or  a  furfurane  ring. 

The  formulae  of  methebenine  and  of  thebenine  can  therefore  be 
resolved  as  follows: 

CiQHio(O.CH3)2(OH)(NH.CH3);  Ci6Hio(OH)2(O.CH3)(NH.CH3) 

Methebenine.  Thebenine. 

The  presence  of  an  OH  group  in  methebenine  was  also  shown  by 
the  preparation  of  the  methyl  ether  of  the  base.  For  this  purpose 
the  base  was  converted  into  the  iodomethylate  of  methyl  methebenine 
and  the  iodomethylate  treated  with  dimethylsulphate  in  alkaline 
solution.  Under  these  conditions  the  hydrogen  of  the  OH  group  is 
replaced  by  a  methyl  group  and  the  iodine  atom  of  the  OH3I  group  is 
replaced  by  the  anion  of  the  methylsulphuric  acid  : 


Ci6Hio(O.CH3)2(OH).N(CH3)3I 

Ci6Hio(O.CH3)3.N(CH3)3.(S04.CH3)  +  HI. 

This  salt  of  methyl  sulphuric  acid  can  be  converted  into  the 
corresponding  iodide  by  means  of  a  concentrated  solution  of  potas- 
sium iodide: 

Ci6Hio(O.CH3)3N(CH3)3.S04.CH3  +  KI  _  = 
Ci6Hio(O.CH3)3.N(CH3)3I  +  KCH3S04. 

When  this  methylated  methebeninemethine  methyl  iodide  is  heated 
with  alkali  trimethylamine  is  eliminated  and  an  nnsatu  rated  deriva- 
tive of  phenanthrene  is  formed  which  contains  three  methoxyl 
groups  : 

Ci6Hio(O.CH3)3.N)CH3)3L  =  N(CH8)s  +  HI+Ci4H0(O.CH8)8.CH=CHs!. 

This  unsaturated  phenanthrene  derivative  can  be  easily  oxidized 
to  a  trimethoxyphenanthrene  carhoxylic  acid 

Ci4H6(O.CH3)3.CH  =  CH2  ---  >  Ci4H0(O.CH3)3.CO.OH 

The  formation  of  a  trimethoxy  derivative  of  phenanthrene  from 
the  methylated  methebenine  shows  that  the  three  oxygen  atoms  of 
methebenine  must  all  be  in  the  phenanthrene  nucleus. 

On  the  other  hand  the  formation'  of  a  monocarboxylic  acid  from 
the  unsaturated  compound  shows  that  the  group  which  in  the  oxida- 
tion is  replaced  by  the  carboxyl  group  is  not  present  in  the  base  in 


87 

the  form  of  a  ring  complex  (as  in   this  case  we  ought  to  get  a  di- 
carboxylic  acid)  e.  g.  like  following 

) CH2 

<:i4H5(0.('H8)8   }         I 

J CH2 

but  as  an  open  unsaturated  chain  as  follows 

Ci4H«(O.CH8)a-CH  =  CH2 

As  this  unsaturated  group  is  formed  only  after  the  splitting  off 
of  the  amido  residue  it  follows  that  the  nitrogen  atom  in  methe- 
benine  must  also  be  situated  in  this  open  chain.  Hence  the  formula 
of  methebenine  can  be  resolved  into  either  one  of  the  following  ex- 


pressions : 


/\ 


O.CHs' 
O.CHs 
OH 


(VII) 


\/ 


(VIII) 


As  thebaine  was  shown  by  Freuml  to  give  oxyethylmethylamine 
OH.CH2-CH2-NH.CHs,  among-  other  decomposition  products  formula 
(VII)  for  metliebenine  would  seem  to  be  the  more  probable  one. 

According  to  this  phenolic  formula  for  methebenine  the  compound 
which  is  formed  by  splitting  off  trirnethylamine  from  the  quaternary 
iodomethylate  of  methyl  methebenine  (methebenine  methine  methyl 
iodide),  i.  e.,  methebenol  ought  still  to  contain  the  OH  group  present 
in  methebenine  and  ought  therefore  to  be  soluble  in  alkalies.  Besides 
we  ought  also  to  expect  that  this  methebenol  .would  contain  the 
unsaturated  group  CH==CH2  just  like  the  compound  obtained  from 
the  methylated  methebenine  niethine  methyliodide. 

The  reaction  ought  to  go  according  the  following  scheme: 


Methebenine  niethine  methyl  iodide 

Ci4H6(O.CH3)2.0H.CH  =  CH2  +  N(CH8)s  +  HI 
Methebenol 

But  as  methebenol  is  insoluble  in  alkalies  and  does  not  contain 
an  unsaturated  CH  =  CHo  group  we  must  assume  that  in  the  form- 
ation of  methebenol  from  the  quaternary  base  there  is  an  internal 
rearrangement  of  the  OH  group  and  the  vinyl  rest  with  the  forma- 
tion of  a  furfurane  ring: 

CH2 

Ci4H6(O.CH3)2  OH.CH:CIk>  --  >  PnH*{O.CH»)*^C.B2 

O 

Methebenol 

(VI) 

The  tendency  to  form  this  ring  is  so  great  that  when  the  above 
mentioned  trimethoxyvinyl  phenanthrene  is  reorystallized  from 
glacial  acetic  acid  one  methoxyl  group  is  saponified  and  the  result- 
ing compound  is  identical  with  methebenol  : 

(CHs.O)  CHo 

CuHo(O.CH3)2(  +H20  =  Ci4ll6(O.CH3)2( 

CH=rCH2  O 

Triniethoxyvinylphenanthrene  Methebenol 

(VI) 


80 

The  same  formation  of  the  furfurane  ring  takes  place  when  the 
trimethoxyvinylphenanthrene  is  treated  with  bromine:  the  resulting 
compound  has  the  composition  of  brommethebenol. 

O.CH«  CHBr 


O 
Trimethoxyvinylplieiianthrene  Brommethebenol 

The  authors  have  so  far  not  succeeded  in  establishing  the  'posi- 
tion of  the  ring  forming  groups  in  the  phenanthrene  complex. 

Experimental.  The  methebenine  hydrochloride  was  prepared 
by  heating  a  solution  of  thebaine  in  methyl  alcohol  containing 
hydrochloric  acid  gas  to  100°.  It  is  difficult  to  obtain  the  free 
methebenine  in  crystalline  form,  but  a  crystalline  sulphate  of  the 
base  can  be  made  by  adding  sulphuric  acid  to  a  strong  solution  of 
methebenine  in  alcohol. 

If  to  a  strong  solution  of  methebenine  hydrochloride  (1  in  40) 
from  two  to  six  molecules  of  normal  sodium  hydroxide  be  added  the 
sodium  salt  of  methebenine  is  precipitated  in  a  gelatinous  condition. 
Upon  addition  of  water  the  precipitate  goes  into  solution.  From  a 
dilute  solution  of  the  hydrochloride  (1  in  200)  the  free  base  is  pre- 
cipitated in  amorphous  condition  upon  the  addition  of  one  molecule 
of  normal  sodium  hydroxide.  On  prolonged  standing  or  slow  addi- 
tion of  more  sodium  hydroxide  the  base  assumes  a  crystalline  form 
and  then  goes  into  solution  only  after  the  addition  of  forty  mole- 
cules of  normal  sodium  hydroxide. 

The  freshly  precipitated  amorphous  base  requires  for  complete 
solution  only  six  to  eight  molecules  normal  or  tenth  normal  sodium 
hydroxide.  The  sodium  salt  and  the  alkaline  solution  of  the  base 
are  not  stable. 

The  diacetyl  methebenine  and  the  dibenzoyl  methebenine  were  ob- 
tained by  adding  sodium  hydroxide  to  a  very  dilute  solution  of 
methebenine  hydrochloride  and  shaking  the  solution  with  acetic 
anhydride  or  benzoylchloride  respectively. 

The  methyl  ether  of  methebenine  methine  methyl  iodide  (dimethe- 
benine  iodomethylate)  could  not  be  obtained  by  the  action  of  methyl- 


iodide  and  sodium  alcoliol*ite  upon  inet.hebenine  at  1()()°.  Ikder 
these  conditions  a  mixture  of  methebenol  and  metliebenine  iodo- 
methylate  is  obtained  from  which  both  these  substances  could  be 
isolated  and  separated  from  each  other  by  means  of  ether. 

An  attempt  to  get  the  methyl  ether  by  means  of  diazomethaiir 
also  gave  negative  results. 

The  ether  was  at  last  obtained  by  treating  metliebenine  methine 
iodomethylate  (which  as  said  above  contains  a  phenolic  OH  group 
and  is  therefore  soluble  in  alkalies)  with  dimethyl  sulphate  in  pre- 
sence of  sodium  hydroxide  and  warming  the  mixture  on  the  water 
bath.  Under  these  conditions  the  OH  group  is  methylated  and  the 
iodine  atom  of  the  CHal  group  is  replaced  by  the  group  SOa.O.CHs. 

When  the  methyl  ether  of  metliebenine  methine  methylsulphate 
obtained  in  this  way  is  warmed  with  a  concentrated  solution  of 
potassium  iodide  the  methyl  ether  of  metliebenine  methine  iodo- 
methylate is  formed. 

The  trimethoxyvinylphenanthrene^  Ci4He(O.CH8)8.CH  —  ('HL>,  was 
obtained  by  boiling  either  the  iodide  or  the  methylsulphate  of  the 
methyl  ether  of  metliebenine  methine  with  potassium  hydrate  for  one 
hour.  After  the  elimination  of  trimethylamine  the  liquid  on  cooling 
deposits  a  green  mass  of  trimethoxyvinylphenanthrene  which  can  be 
recrystallized  from  alcohol. 

The  trimethoxyvinyrphenanthrene  combines  with  picric  acid  when 
both  are  mixed  together  in  alcoholic  solution.  The  picrate  is  not 
very  stable  and  can  be  recrystallized  from  alcohol  only  in  presence 
of  some  picric  acid. 

The  trimethoxyvinylphenanthrene  carboxylic  acid,  CiiHe 
(O.CHs)8.CO.OH,  was  prepared  by  oxidizing  tlie  trimethoxyvinyl- 
phenanthrene in  acetone  solution  with  potassium  permanganate. 
After  filtering  off  the  MnOo  the  liquid  was  saturated  with  sodium 
chloride  and  shaken  out  with  ether.  The  yield  is  about  10  per  cent 
of  theory. 

The  conversion  of  trimethoxyvinylphenanthrene  into  methebenol 
(VI)  can  be  accomplished  either  by  boiling  the  trimethoxyvinyl- 
phenanthrene for  a  few  minutes  with  glacial  acetic  acid  or  by  adding 
to  a  boiling  alcoholic  solution  of  trimethoxyvinylphenanthrene  con- 
centrated hydrochloric  acid  drop  by  drop  till  the  liquid  becomes 
turbid. 


01 

It  was  shown  tli;it  methebenol  contains  only  two  CII.-jO  groups, 
heiiee  one  ol'  the  CII;>,()  groups  of  trimet  hoxy  vinylphemmthrene  is 
eliminated  as  methyl  alcohol  in  (he  dosing  of  the  furfurane  ring. 

\\hen  trimot -liox yvinylphena ,n throne  is  treated  witli  bromine  a 
mouobro  linnet  hebenol  is  formed  together  with  some  more  brominated 
compound.  The  monobrommethebenol  was  also  found  to  contain 
only  two  ('!!:{()  groups  showing  that  one  of  the  CHaO  groups  of 
trimethoxyvinylpbenanthrene  is  eliminated  as  methyl  bromide. 

Her.  Dtsch.  Chem.  Ges.,  1904,  27*0. 

Xanthine  Bases.  W.  Trail  be  haw  devised  the  following  syn- 
theses for  hypoxanthine  and  adenine. 


On  boiling  an  alcoholic  solution  of  sodium  ethyl- 
cyano  acetate  with  sulphourea  alcohol  is  split  off  and  a  ditfiniltly 
soluble  sodium  salt  of  4-a,mino-(>,  oxy-2,  thiopyrimidine  separates 
out  from  which  the  free  base  can  be  liberated  by  acetic  acid 

ML-  CO.O.CsMa  'NH 6(!(> 

is     +      I'll                                "CS  *CH 

ML'          CN  SNH -*C  =  NH 

Ktbyloyanoacetate  4,  awino-6,  oxy-2,  t.liiopyriuiidine 

This  pyrimidine  compound  reacts  with  nitrous  acid  giving  an 
isonitroso  derivative  which  by  reduction  is  converted  into  4,  f>, 
diamino-0,  oxy-2,  thiopyrimidine 


NH 


CS  C  —  N.OH 

I 
NH 


II 
-  —  C  =  N 


Iso  nitroao  derivative  4,  5,  diainiiio-C),,  oxy-2,  thiopyriraidine 

When  the  diamino  compound  is  boiled  with  formic  acid  a  form  v  I 
derivative  is  formed  which  when  heated  to  250°  loses  one  molecule 
water  and  is  converted  into  2,  thiohypoxanthine 


92 

XH CO  XH CO 

i    '  I  II 

CS  C.NH.HCO       =====        H20+    (S  C.XH 

NH C.NH2  XH C.X  ^CH 

Formyl  derivative  2,  Thioliypoxantliine 

When  this  thiohypoxanthine  is  treated  with  nitric  acid  the  sul- 
phur is  eliminated  quantitatively  as  sulphuric  acid  and  hypoxanthine 
is  formed  identical  with  the  natural  base 


ADENINE.  On  treating-  methylene  cyanide  (malonitril)  with  thio 
urea  in  presence  of  sodium  ethylate  in  alcoholic  solution  a  compound 
is  formed  which  can  be  regarded  as  4,  6-diamido-2,  thiopyrimidine 

NH2          CEEN  ix==6C.XH:>  XH  -  C=XH 

i          i    •  i  -       i  L      .  i 

CS      +      CH2       =====       2C.SH     *CH  or          (S  CH2 

II  il  H  II 

NH2  C=N  SN  -  *C.NHa  XH  --  C  =  XH 

By  means  of  nitrous  acid  the  diainido  compound  can  be  con- 
verted into  an  isonitroso  derivative  which  by  reduction  is  converted 
into  4,  5,  6-triamino-2,  thiopyrimidine 

X  H  -  -C  -  XH  X=--C.XH2 

CS  C  =  N.OH  +  HH    =====    C.SH    CNH2  +  H2O 

II  II 

NH  --  C  =  NH  X  --  C.XH2 

Iso  tiitroso  derivative  -i,  5,  6-Triamino-^,  thioi)yriinidinp 

This  pyrimidine  derivative  is  changed  b}7  formic  acid  into  the 
corresponding  formyl  compound  which  on  boiling'  loses  water  and  is 
converted  into  2,  thioadenine 


-II  II 

C.SH     C.NH.HCO  ===     H2O  +  CS          C  -  XH 
II  \C1I 

X  --  C.XH2  XH  -  C        XVU 

2,  Thioadenine 


93 

From  this  thioadenine  the  sulphur  cannot  be  eliminated  by 
means  of  nitric  acid  as  is  the  case  of  the  corresponding  hypoxanthine 
compound,  but  hydrogen  peroxide  converts  the  thioadenine  very 
easily  into  adenine  eliminating  the  sulphur  quantitatively 


n| 

N—  -C  -  N/J 

Adenine 

Anrial.  (Lieb.)  331,  64. 

Yohimbine.  L.  Spiegel  in  collabration  with  B.  Auerbach  have 
investigated  the  alkaloid  yohimbine  obtained  from  Yohimbo  bark. 

The  alkaloid  has  the  formula,  (^HsoNaCU,  but  under  certain  con- 
ditions it  loses  one  molecule  water  forming  anhydroyohimbine, 
CjteHasN-gOjB.  The  latter  formula  Underlies  the  salts  of  the  alkaloid. 

On  treating  yohimbine  with  alkali  the  alkaloid  is  converted  into 
yohimboic  acid  (noryohimbine). 

Yohimboic  acid  is  both  a  monobasic  acid  and  a  mono-acid  base 
and  has  the  formula  C-zoH-jeN^CU. 

On  treating  yoliiinboic  acid  with  hydrochloric  acid  gas  in  the 
presence  of  alcohols  the  hydrochlorides  of  new  compounds  are  formed 
in  which  two  hydrogen  atoms  have  been  replaced  by  two  alkyl 
groups  and  from  which,  in  the  case  of  the  lower  alcohols,  one  mole* 
cule  of  water  has  at  the  same  time  been  eliminated.  Hence  the 
hydrochloride  obtained  when  methyl  alcohol  is  used  has  the  formula 
C22H2sN203.HCl  and  is  identical  with  the  salt  obtained  from  yohim- 
bine by  means  of  hydrochloric  acid. 

With  isobutyl  alcohol  there  is  no  elimination  of  water  and  the 
compound  obtained  has  therefore  the  formula  CasBUaNaO^HCl. 

The  free  base  underlying  these  compounds  can  be  obtained  from 
these  hydrochlorides  by  dissolving  them  in  water  and  adding  am- 
monia, to  the  solution. 

As  yoliiinboic  acid  is  a  monobasic  acid  it  ought  to  take  up  only 
one  alkyl  group  in  the  reaction  with  hydrochloric  acid  gas  in  presence 
of  alcohols. 

It  is  possible  (though  har,dly  probable)  thatonepf  the  alkyl 
groups  attaches  itself  to  the  nitrogen  atom^f^SS^SclJ^HL  such  be 

7        >     OF  THE     '      ^^ 

UNIVERSITY 

OF 


94 

the  case  we  would  have  to  assume  that  in  the  conversion  of  yohim- 
bine  into  yohimboic  acid  both  the  methyl  group  present  in  the  car- 
boxyl  group  and  the  methyl  group  attached  to  the  nitro^  a  atom 
are  eliminated.  While  experiment  has  shown  that  both  a  methoxyl 
group  and  a  methylimide  group  are  present  in  yohimboiic  acid  it  is 
nevertheless  difficult  to  suppose  that  in  the  conversion  of  yohimbine 
into  yohimboic  acid  a  methyl  group  attached  to  nitrogen  is  so 
easily  split  off. 

The  author  hopes  to  clear  up  the  subject  by  means  of  the  reac- 
tion of  diazomethane  upon  yohimboic  acid. 

In  this  reaction  there  are  formed  two  different  substances  both 
of  which  are  converted  into  yohimbine  when  treated  with  hydro- 
chloric acid  in  presence  of  methyl  alcohol. 

Ber.  Dtsch.  Chem.  Ges.,  1904. 
Northwestern  University  School  of  Pharmacy. 


""f" 

l/Q 


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twice  by  its  author,  Dr.  Fr.  Hoffmann.    Price,  £0.50. 

2.  Reagents  and  Reactions   known   by   the  names  of  their  authors. 

Based  on  the  original  collection  of  A.  Schneider;  revised  and  en- 
larged by  Dr.  Julius  Altschul;  translated  from  the  German  by  Dr. 
Kichard  Fischer,  Asst.  Professor  of  Practical  Pharmacy  at  the 
University  of  Wisconsin.  Although  imperfect  in  many  respects,  this 
compilation  has  proven  a  convenient  aid  in  the  laboratory  and  on 
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on  hand  can  be  had  for  $0.15. 

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being  revised. 

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stracts by  Dr.  H.  M.  Gordin.    Pamphlet,  pp.  40.    $0.30. 

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BIBLIOGRAPHIES. 


1.  Chemical  Biography  of  Morphine.    From  1875  to  1897, 

with  an  index  of  authors  and  subject  index.    By  H.  E.  Brown. 
Pamphlet,  pp.  60.  $0.40 

2.  Santonin.    Bibliography,    with   abstracts   of   methods    of   pro- 

duction etc.    From  1830  to  1897.     By  A.   Van  Zwaluwen- 
burg.    Pamphlet,  pp.  11.  0.10 


3.    Bibliography   of  Apiol.    From  1855  to  1896.    By  A.  Van 
Zwaluwenburg.    Pamphlet,  pp.  4. 


0.05 


4-.    Bibliography    of  Spirit    of   nitrous   ether,    and    ethyl 
nitrite.     Up   to   1899.      By   W.  0.   Richtmann    and    J.    A. 
Anderson.    Brochure,  pp.  180.  1.00 

5.    Bibliography    of    aromatic    waters.    From    1809    to    1900 

inch    By  W.  0.  Richtmann.    Brochure,  pp.  219.  1.00 

In  addition  to  the  pamphlet  form,  these  bibliographies  will  be  found 
very  convenient  for  card  catalogues  which  can  be  kept  up  to  date  aa  indi- 
cated by  the  following  fascimile  reproduction  of  such  a  card. 


Jj  iAJ*** 
OVERDUE. 


